In medical studies, endpoints are often measured for each patient longitudinally. The mixed-effects model has been a useful tool for the analysis of such data. There are situations in which the parameters of the model are subject to some restrictions or constraints. For example, in hearing loss studies, we expect hearing to deteriorate with time. This means that hearing thresholds which reflect hearing acuity will, on average, increase over time. Therefore, the regression coefficients associated with the mean effect of time on hearing ability will be constrained. Such constraints should be accounted for in the analysis. We propose maximum likelihood estimation procedures, based on the expectation-conditional maximization either algorithm, to estimate the parameters of the model while accounting for the constraints on them. The proposed methods improve, in terms of mean square error, on the unconstrained estimators. In some settings, the improvement may be substantial. Hypotheses testing procedures that incorporate the constraints are developed. Specifically, likelihood ratio, Wald, and score tests are proposed and investigated. Their empirical significance levels and power are studied using simulations. It is shown that incorporating the constraints improves the mean squared error of the estimates and the power of the tests. These improvements may be substantial. The methodology is used to analyze a hearing loss study.

Multivariate outcomes are often measured longitudinally. For example, in hearing loss studies, hearing thresholds for each subject are measured repeatedly over time at several frequencies. Thus, each patient is associated with a multivariate longitudinal outcome. The multivariate mixed-effects model is a useful tool for the analysis of such data. There are situations in which the parameters of the model are subject to some restrictions or constraints. For example, it is known that hearing thresholds, at every frequency, increase with age. Moreover, this age-related threshold elevation is monotone in frequency, that is, the higher the frequency, the higher, on average, is the rate of threshold elevation. This means that there is a natural ordering among the different frequencies in the rate of hearing loss. In practice, this amounts to imposing a set of constraints on the different frequencies' regression coefficients modeling the mean effect of time and age at entry to the study on hearing thresholds. The aforementioned constraints should be accounted for in the analysis. The result is a multivariate longitudinal model with restricted parameters. We propose estimation and testing procedures for such models. We show that ignoring the constraints may lead to misleading inferences regarding the direction and the magnitude of various effects. Moreover, simulations show that incorporating the constraints substantially improves the mean squared error of the estimates and the power of the tests. We used this methodology to analyze a real hearing loss study.

There are often situations where two or more regression functions are ordered over a range of covariate values. In this paper, we develop efficient constrained estimation and testing procedures for such models. Specifically, necessary and sufficient conditions for ordering generalized linear regressions are given and shown to unify previous results obtained for simple linear regression, for polynomial regression and in the analysis of covariance models. We show that estimating the parameters of ordered linear regressions requires either quadratic programming or semi-infinite programming, depending on the shape of the covariate space. A distance-type test for order is proposed. Simulations demonstrate that the proposed methodology improves the mean square error and power compared with the usual, unconstrained, estimation and testing procedures. Improvements are often substantial. The methodology is extended to order generalized linear models where convex semi-infinite programming plays a role. The methodology is motivated by, and applied to, a hearing loss study.Key words: constrained inference, quadratic programming, semi-infinite programming Theoretical foundationThe development of estimation and testing procedures for ordered regressions requires the reformulation of the hypotheses (2) in terms of the parameters of the model (1). It turns © 2017 Board of the Foundation of the Scandinavian Journal of Statistics. Scand J Statist 44Ordered regressions 819 out that the shape of the covariate space X plays an important role in determining the constraints required for ordering regressions. In the following, necessary and sufficient conditions for ordering regressions are provided. These are followed by a discussion of implications, applications and some specific examples.