A Cox Model for Biostatistics of the Future

Professor Sir David R. Cox (DRC) is widely acknowledged as among the most important scientists of the second half of the twentieth century. He inherited the mantle of statistical science from Pearson and Fisher, advanced their ideas, and translated statistical theory into practice so as to forever change the application of statistics in many fields, but especially biology and medicine. The logistic and proportional hazards models he substantially developed, are arguably among the most influential biostatistical methods in current practice. This paper looks forward over the period from DRC\u27s 80th to 90th birthdays, to speculate about the future of biostatistics, drawing lessons from DRC\u27s contributions along the way. We consider Cox\u27s model of biostatistics, an approach to statistical science that: formulates scientific questions or quantities in terms of parameters gamma in probability models f(y; gamma) that represent in a parsimonious fashion, the underlying scientific mechanisms (Cox, 1997); partition the parameters gamma = theta, eta into a subset of interest theta and other nuisance parameters eta necessary to complete the probability distribution (Cox and Hinkley, 1974); develops methods of inference about the scientific quantities that depend as little as possible upon the nuisance parameters (Barndorff-Nielsen and Cox, 1989); and thinks critically about the appropriate conditional distribution on which to base infrences. We briefly review exciting biomedical and public health challenges that are capable of driving statistical developments in the next decade. We discuss the statistical models and model-based inferences central to the CM approach, contrasting them with computationally-intensive strategies for prediction and inference advocated by Breiman and others (e.g. Breiman, 2001) and to more traditional design-based methods of inference (Fisher, 1935). We discuss the hierarchical (multi-level) model as an example of the future challanges and opportunities for model-based inference. We then consider the role of conditional inference, a second key element of the CM. Recent examples from genetics are used to illustrate these ideas. Finally, the paper examines causal inference and statistical computing, two other topics we believe will be central to biostatistics research and practice in the coming decade. Throughout the paper, we attempt to indicate how DRC\u27s work and the Cox Model have set a standard of excellence to which all can aspire in the future

Inference Based on Estimating Functions in the Presence of Nuisance Parameters

In many studies, the scientific objective can be formulated in terms of a statistical model indexed by parameters, only some of which are of scientific interest. The other "nuisance parameters" are required to complete the specification of the probability mechanism but are not of intrinsic value in themselves. It is well known that nuisance parameters can have a profound impact on inference. Many approaches have been proposed to eliminate or reduce their impact. In this paper, we consider two situations: where the likelihood is completely specified; and where only a part of the random mechanism can be reasonably assumed. In either case, we examine methods for dealing with nuisance parameters from the vantage point of parameter estimating functions. To establish a context, we begin with a review of the basic concepts and limitations of optimal estimating functions. We introduce a hierarchy of orthogonality conditions for estimating functions that helps to characterize the sensitivity of inferences to nuisance parameters. It applies to both the fully and partly parametric cases. Throughout the paper, we rely on examples to illustrate the main ideas

Longitudinal data analysis using generalized linear models”.

SUMMARY This paper proposes an extension of generalized linear models to the analysis of longitudinal data. We introduce a class of estimating equations that give consistent estimates of the regression parameters and of their variance under mild assumptions about the time dependence. The estimating equations are derived without specifying the joint distribution of a subject's observations yet they reduce to the score equations for multivariate Gaussian outcomes. Asymptotic theory is presented for the general class of estimators. Specific cases in which we assume independence, m-dependence and exchangeable correlation structures from each subject are discussed. Efficiency of the proposed estimators in two simple situations is considered. The approach is closely related to quasi-likelihood

Feedback Models for Discrete and Continuous Time Series

In public health research, it is common to follow a cohort of subjects over time, observing a vector of health indicators and a set of covariates at each of many visits. An objective of analysis is to characterize the inter-dependencies, in particular, the feedback of one response upon another while accounting for the covariates. With Gaussian responses, multivariate autoregressive models that incorporate feedback are commonly used. This paper discusses analogous Markov models for multivariate discrete and mixed discrete/continuous response variables. One special case is an extension of seemingly unrelated regressions to discrete and continuous outcomes. A generalized estimating equations approach that requires correct specification of only conditional means and variances is discussed. The methods are illustrated by a study of infectious diseases and vitamin A deficiency in Indonesian children