Direct and Indirect Causal Effects via Potential Outcomes*

Abstract. The use of the concept of ‘direct’ versus ‘indirect’ causal effects is common, not only in statistics but also in many areas of social and economic sciences. The related terms of ‘biomarkers’ and ‘surrogates’ are common in pharmacological and biomedical sciences. Sometimes this concept is represented by graphical displays of various kinds. The view here is that there is a great deal of imprecise discussion surrounding this topic and, moreover, that the most straightforward way to clarify the situation is by using potential outcomes to define causal effects. In particular, I suggest that the use of principal stratification is key to understanding the meaning of direct and indirect causal effects. A current study of anthrax vaccine will be used to illustrate ideas.     

The Reparative Motive in Surrogate Mothers

ABSTRACT

This paper explores the motivations of surrogate mothers, with a focus on the underlying reparative motive. An overview of the typical surrogate's characteristics and personality, the theoretical underpinnings of the reparative motive, and the tension between reparation and loss in the surrogate are considered. Clinical material from psychological evaluations of women pursuing a surrogate pregnancy is presented to illustrate.     

ASSESSING THE RELATIONSHIP BETWEEN SYMPTOMS OF ALLERGIC RHINOCONJUNCTIVITIS AND POLLEN COUNTS

The relationship between daily pollen counts during the peak pollen season and hay fever symptoms in known sufferers of pollen allergy was investigated in a Sydney hospital‐based study. This paper develops statistical models for both the short term (day to day) associations and the longer term relationships between these time series. Possible effects of asthma status are investigated. The analyses illustrate how different relationships between time series may be explored in a simple way by working on different time scales with suitably transformed variables.     

Evaluating surrogate variables for improving microarray multiple testing inference

The use of surrogate variables has been proposed as a means to capture, for a given observed set of data, sources driving the dependency structure among high-dimensional sets of features and remove the effects of those sources and their potential negative impact on simultaneous inference. In this article we illustrate the potential effects of latent variables on testing dependence and the resulting impact on multiple inference, we briefly review the method of surrogate variable analysis proposed by Leek and Storey (PNAS 2008; 105:18718-18723), and assess that method via simulations intended to mimic the complexity of feature dependence observed in real-world microarray data. The method is also assessed via application to a recent Merck microarray data set. Both simulation and case study results indicate that surrogate variable analysis can offer a viable strategy for tackling the multiple testing dependence problem when the features follow a potentially complex correlation structure, yielding improvements in the variability of false positive rates and increases in power.     

鲍照“代”乐府体探析 ——兼论汉魏乐府创作传统的特征

《鲍照集》里的代乐府是乐府创作中的一个特殊现象,鲍照的代乐府虽然具有汉魏乐府创作传统的基本特质和不少表现元素,但并非汉魏乐府的复旧。“代”字标示了他在传统基础上的创变。 在《鲍照集》里的代乐府或借旧题裁己意,或用新题代旧题,标示了鲍照拟乐府与汉魏晋乐府创作传统的联系和区别。认识代乐府体所提供的考察角度,便于今人更清楚地看到鲍照对于汉魏古乐府传统和当时新兴乐府的不同,以及处理各种乐府体式的不同创作态度。鲍照的代乐府以五言为多,集中体现了他对汉魏晋乐府创作传统的认识：第一,取题多用旧题,小部分自立新题;第二,鲍照的代乐府五言中有一部分吸取了汉乐府偏重叙事以及场景表现单一性的方式,通过某个人物、场景或者故事的设计,集中地抒发自己的感想;第三,多用比兴虽是汉魏古诗共同的表现特征,但鲍照有一部分乐府的比兴句式更接近汉乐府;第四,汉古诗和乐府好从人生感慨和人生经验中总结出某些名理,富有训诫意味,鲍照也时有这类总结性的诗句;第五,鲍照的代乐府文气贯通流畅,虽然有些作品已不免俳偶铺陈,但没有两晋古诗的抽象议论,尤其是开头和结尾大体能够保持汉魏乐府的语言风格。当然,鲍照的代乐府最关键的还是抒情视角的普世性,即无论其中包含了多少个人寄托,基本上仍是采用代言体以及与此相应的传统抒情主题：鲍照代乐府古题的抒情都是从普世性的感受出发,所以这些代乐府题的主题内容都不出于生死感叹、去乡远游、人情亲疏、离别相思、从军赴边、游览京洛等汉魏乐府的传统题目范围,没有具体而特定的事件或背景的交代,没有倾诉感情的具体对象,触发感叹的真实原因隐藏在巧妙的比兴以及那些虚构的人物和场景之中,个人特殊的思想矛盾若隐若现地寄寓在人们共同的感受之中。 总之,鲍照的代乐府反映了鲍照对于汉魏乐府的体式及其创作特征的深刻体认,为唐代乐府学习汉魏乐府提供了宝贵的经验。他在代乐府中的创变,特别是乐府古诗化的倾向,带来了乐府表现视角的变化,对于李白的古题乐府产生了深远的影响。     

STATISTICAL CHALLENGES OF AIDS: (The 1990 Knibbs Lecture, Canberra, 27 November 1990)

Issues that are central to the understanding and management of the HIV epidemic have generated numerous statistical challenges. This paper considers questions concerning the incubation period, the effects of treatments, pre diction of AIDS cases, the choice of surrogate end points for the assessment of treatments and design of strategies for screening blood samples. These issues give rise to a broad range of intriguing problems for statisticians. We describe some of these problems, how they have been tackled so far and what remains to be done. The discussion touches on topical statistical methods such as smoothing, bootstrapping, interval censoring and the ill-posed inverse problem, as well as asking fundamental questions for frequentist statistics.     

Grandparent Caregivers' Perception of the Stress of Surrogate Parenting

Abstract

This paper examined the relationship between sociodemo-graphic factors, Stressors, and resources, and the perception of stress by grandparents caring for their grandchildren. A sample of 129 grandparents had face-to-face interviews. A hierarchical block regression analysis produced a model that accounted for 49 percent of the variance. For the first block (sociodemographic factors) younger age and being white were significant, but in the context of the second block, these variables disappeared and being employed, having conflict with the grandchildren's parent, and grandchild problems were significant. The final block, in which resources were added, found that being employed, having conflict with the children's parent, grandchild problems, and lack of family resources were associated with high perception of stress. These findings suggest strategies for social work intervention.     

Potential surrogate endpoints in cancer research – some considerations and examples

We present an introductory survey of the use of surrogates in cancer research, in particular in clinical trials. The concept of a surrogate endpoint is introduced and contrasted with that of a biomarker. It is emphasized that a surrogate endpoint is not universal for an indication but will depend on the mechanism of treatment. We discuss the measures of validity of a surrogate and give examples of both cancer surrogates and biomarkers on the path to surrogacy. Circumstances in which a surrogate endpoint may actually be preferred to the clinical endpoint are described. We provide pointers to the recent substantive literature on surrogates. Copyright © 2009 John Wiley & Sons, Ltd.     

An investigation into the two‐stage meta‐analytic copula modelling approach for evaluating time‐to‐event surrogate endpoints which comprise of one or more events of interest

Clinical trials of experimental treatments must be designed with primary endpoints that directly measure clinical benefit for patients. In many disease areas, the recognised gold standard primary endpoint can take many years to mature, leading to challenges in the conduct and quality of clinical studies. There is increasing interest in using shorter‐term surrogate endpoints as substitutes for costly long‐term clinical trial endpoints; such surrogates need to be selected according to biological plausibility, as well as the ability to reliably predict the unobserved treatment effect on the long‐term endpoint. A number of statistical methods to evaluate this prediction have been proposed; this paper uses a simulation study to explore one such method in the context of time‐to‐event surrogates for a time‐to‐event true endpoint. This two‐stage meta‐analytic copula method has been extensively studied for time‐to‐event surrogate endpoints with one event of interest, but thus far has not been explored for the assessment of surrogates which have multiple events of interest, such as those incorporating information directly from the true clinical endpoint. We assess the sensitivity of the method to various factors including strength of association between endpoints, the quantity of data available, and the effect of censoring. In particular, we consider scenarios where there exist very little data on which to assess surrogacy. Results show that the two‐stage meta‐analytic copula method performs well under certain circumstances and could be considered useful in practice, but demonstrates limitations that may prevent universal use.