On asymptotic non-normality of null distributions of mrpp statistics

Severe departures from normality occur frequently for null distributions of statistics associated with applications of mulLi-response permutation procedures (MRPP) for either small or large finite populations. This paper describes the commonly encountered situation associated with asymptotic non-normality for null distributions of MRPP statistics which does not depend on the underlying multivariate distribution. In addition, this paper establishes the existence of a non-degenerate underlying distribution for which the null distributions of MRPP statistics are asymptotically non-normal for essentially all size structure configurations. It is known that MRPP statistics are symmetric versions of a broader class of statistics, most of which are asymmetric. Because of the non-normality associated with null distributions of MRPP statistics, this paper includes necessary results for inferences based on the exact first three moments of anv statistic in this broader class (analogous to existing results for MRPP statistics).     

Computation of finite population parameters and approximate probability values for multi-response randomized block permutation procedures (mrbp)

An algorithm is presented for computing the finite population parameters and the approximate probability values associated with a recently-developed class of statistical inference techniques termed multi-response randomized block permutation procedures (MRBP).     

Closed competitive bidding

This paper replaces the competitive bidding models of Friedman and Gates with a more general probabalistic bidding model which resolves the conflict between them. The validity of the model is demonstrated by simulation. Practical difficulties of using the probabalistic approach are discussed and several lines of future research suggested.     

Computation of exact probability values for multi-response permutation procedures (MRPP)

An algorithm is presented for computing the exact probability value associated with a recently–developed class of statistical inference techniques termed multi–response permutation procedures (MRPP).     

Historical epidemiology of smallpox in Åland,Finland: 1751–1890

We analyze a 140-year series of smallpox deaths in the Åland Islands, Finland. Vaccination, introduced in 1805, dramatically reduced the annual number of smallpox deaths. It also influenced the age distribution of smallpox deaths, changing smallpox from a childhood disease before 1805 to one which affected both adults and children after 1805. This appears to be due to the fact that Ålanders were usually vaccinated only once during childhood and often lost their immunity during adulthood. Spectral analysis of the prevaccination time series of smallpox deaths demonstrates a strong seven-year periodicity, reflecting the amount of time necessary to build up a cohort of nonimmune individuals. After the introduction of vaccination, the periodicity changes to eight years. The probability that a parish in Åland was affected by a smallpox epidemic is shown to be highly correlated with migration patterns and parish population sizes.     

Asymptotic normality of MRPP statistics from invariance principles of u-statistics

Multi-response permutation procedures (MRPP) were recently introduced to test differences between a priori classified groups of objects ( Mielke, Berry Johnson, 1976; Mielke, 1979 ). The null distributions of the MRPP statistics were initially conjectured to be asymptotically normal for some specified conditions within the setting of a sequence of finite populations due to Madow ( 1948 ).

Asymptotic normality of a class of MRPP statistics (under the null hypothesis) is shown in two cases: (i) the setting which considers the populations to be the samples resulting from sequential independent identically distributed (i.i.d.) sampling (sampling from infinite populations) and (ii) the setting of a sequence of increasingly large finite populations (sampling from finite populations). The results are direct applications of the weak convergence of a U-statistic process in the i.i.d. case to a Brownian motion (Bhattacharyya and Sen, 1977) and of the weak convergence of a U-statistic process in the finite populations case to a Brownian bridge (Sen, 1972). The conditions are milder for the i.i.d. case than for the finite populations case. However, neither case provides a restriction of a practical consequence in applications of MRPP. In either case, convergence is shown to depend on the asymptotic ratios of the group sizes to the population size.     

Exact and resampling probability values for the Piccarreta nominal–ordinal index of association

Exact, resampling, and Pearson type III permutation methods are provided to compute probability values for Piccarreta's nominal–ordinal index of association. The resampling permutation method provides good approximate probability values based on the proportion of resampled test statistic values equal to or greater than the observed test statistic value.     

Longitudinal assessment of the impact of multiple switches between a biosimilar and its reference product on efficacy parameters

Patients, physicians, and health care providers in Europe have more than 10 years of experience with biosimilars. However, there are still debates if switching between a biosimilar and its reference product influences the efficacy of the treatment. In this paper, we address this uncertainty by developing a formal statistical test that can be used for showing that switching has no negative impact on the efficacy of biosimilars. For that, we first introduce a linear mixed‐effects model that is used for defining the null hypothesis (switching influences the efficacy) and the alternative hypothesis (switching has no influence on the efficacy). Using this as the foundation of our work, we propose several approaches for testing for changes in the efficacy of the treatment due to switching and discuss the properties of these tests in an extensive simulation study. It is shown that all these methods have advantages and disadvantages and the decision regarding which method is preferred depends on the expectation of a switching assessment. To demonstrate the applicability of the methods in practice, the approaches were applied to the data of the EGALITY study, which compares the reference product Enbrel® (Amgen) with the approved biosimilar Erelzi® (Sandoz).