Measurement in clinical trials: A neglected issue for statisticians?

Biostatisticians have frequently uncritically accepted the measurements provided by their medical colleagues engaged in clinical research. Such measures often involve considerable loss of information. Particularly, unfortunate is the widespread use of the so‐called ‘responder analysis’, which may involve not only a loss of information through dichotomization, but also extravagant and unjustified causal inference regarding individual treatment effects at the patient level, and, increasingly, the use of the so‐called number needed to treat scale of measurement. Other problems involve inefficient use of baseline measurements, the use of covariates measured after the start of treatment, the interpretation of titrations and composite response measures. Many of these bad practices are becoming enshrined in the regulatory guidance to the pharmaceutical industry. We consider the losses involved in inappropriate measures and suggest that statisticians should pay more attention to this aspect of their work. Copyright © 2009 John Wiley & Sons, Ltd.     

可控制性卵巢刺激治疗中促性腺激素释放激素激动剂降调节与卵巢过度抑制

基于促性腺激素释放激素激动剂(GnRH-a)短时给药对垂体的激发作用引起血清黄体生成素(LH)和卵泡刺激素(FSH)升高有利于增加卵泡募集,而长期给药导致垂体局部受体脱敏与消耗而有效地抑制排卵前LH峰出现和降低卵泡晚期血清LH水平,从而减少卵泡过早黄素化和取消周期、改善卵子质量     

卵巢低反应者体外受精-胚胎移植的临床结局分析

目的评估首次体外受精-胚胎移植时表现为卵巢低反应的患者接受再次体外受精-胚胎移植治疗的实际意义和调整临床处理过程的价值。方法回顾性分析2004年1月至12月间在北京大学第三医院生殖中心进行体外受精-胚胎移植的206个卵巢低反应病例,共288个周期的临床资料。结果206例卵巢低反应病例首次IVF-ET时临床妊娠率为22%。其中82例接受了再次IVF-ET,临床妊娠率为40.6%,高于首次IVF-ET,经统计学检验差异有显著性(P<0.05),再次IVF-ET的E2峰值,取卵数以及移植胚胎数均高于首次IVF-ET,经统计学检验差异有显著性(P<0.05)。结论首次IVF-ET卵巢低反应的患者经过调整促排卵方案,接受再次IVF-ET时临床妊娠率有所提高。     

A Model of First‐responder Coping: An Approach/Avoidance Bifurcation

The work of first responders is fraught with numerous stressors, ranging from potentially traumatic critical incidents to institutional strains. The severity and pervasiveness of these difficulties prompt a necessary consideration of the coping methods employed by first responders. The present study developed an empirical model of first‐responder coping strategies, based upon a nationally representative survey sample of 6240 first responders. Participants were drawn from Swedish first responders in the following occupations: coast guard, customs control, military, emergency medical services, fire department and police services. In the final model, exposure to stress related to well‐being through several indirect paths that in sum accounted for the original direct relationship between these constructs. These several indirect paths were classified theoretically as either approach or avoidance coping behaviours or subsequent health outcomes. In general, approach coping behaviours were related to better well‐being; and avoidance was related to a decrease in the outcome. The size of the present sample, as well as the diverse nature of the included first responders, suggests that the resulting model may offer a unique insight into potentially adaptive pathways for first‐responder coping. Copyright © 2016 John Wiley & Sons, Ltd.     

Model selection based on combined penalties for biomarker identification

The growing role of targeted medicine has led to an increased focus on the development of actionable biomarkers. Current penalized selection methods that are used to identify biomarker panels for classification in high-dimensional data, however, often result in highly complex panels that need careful pruning for practical use. In the framework of regularization methods, a penalty that is a weighted sum of the L₁ and L₀ norm has been proposed to account for the complexity of the resulting model. In practice, the limitation of this penalty is that the objective function is non-convex, non-smooth, the optimization is computationally intensive and the application to high-dimensional settings is challenging. In this paper, we propose a stepwise forward variable selection method which combines the L₀ with L₁ or L₂ norms. The penalized likelihood criterion that is used in the stepwise selection procedure results in more parsimonious models, keeping only the most relevant features. Simulation results and a real application show that our approach exhibits a comparable performance with common selection methods with respect to the prediction performance while minimizing the number of variables in the selected model resulting in a more parsimonious model as desired.     

Effects of transmembrane region variability on cell surface expression and allorecognition of HLA-DP3

The functional relevance of polymorphisms outside the peptide binding groove of HLA molecules is poorly understood. Here we have addressed this issue by studying HLA-DP3, a common antigen relevant for functional matching algorithms of unrelated hematopoietic stem cell transplantation (HSCT) encoded by two transmembrane (TM) region variants, DPB1^*03:01 and DPB1^*104:01. The two HLA-DP3 variants were found at a overall allelic frequency of 10.4% in 201 volunteer stem cell donors, at a ratio of 4.2:1. No significant differences were observed in cell surface expression levels of the two variants on B lymphoblastoid cell lines (BLCL), primary B cells or monocytes. Three different alloreactive T cell lines or clones showed similar levels of activation marker CD107a and/or CD137 upregulation in response to HLA-DP3 encoded by DPB1^*03:01 and DPB1^*104:01, either endogenously on BLCL or after lentiveral-vector mediated transfer into the same cellular background. These data provide, for the first time, direct evidence for a limited functional role of a TM region polymorphism on expression and allorecognition of HLA-DP3 and are compatible with the notion that the two variants can be considered as a single functional entity for unrelated stem cell donor selection.     

Tyranny of distance and rural prehospital care: Is there potential for a national rural responder network?

Critical illness intersects with the workload of rural doctors in Australia, mostly via their on‐call responsibilities to rural hospitals. A significant proportion of these are prehospital incidents – vehicle crashes, farming injuries, bushfire etc. Effective care for such patients requires an integration of prehospital ambulance services, retrieval services and tertiary level trauma services all the way through to rehabilitation. Ambulance services in rural areas are often volunteer based, and with increasing remoteness via the ‘tyranny of distance’ comes the likelihood of increased delay in arrival of specialist retrieval services. Potential exists to utilise rural clinicians to respond to prehospital incidents in certain defined circumstances, as suggested by a recent survey of rural doctors.     

Investigating the ‘placebo personality’ outside the pain paradigm

Aim

To identify personality traits related to placebo responding outside the context of pain.

Methods

Sixty three healthy volunteers completed the study. Personality traits were measured online one week prior to a laboratory session in which two psychosocial stress tests were administered. Prior to the second test, the placebo group received an intranasal spray of ‘serotonin’ (placebo) with the suggestion that it would enhance recovery. Subjective stress, heart rate and heart rate variability were measured. Self reported and physiological responses to the placebo suggestion were assessed against personality variables.

Results

Placebo effects were demonstrated in both self reported and physiological stress metrics. Lower optimism and less empathic concern predicted greater perceived benefits from the placebo treatment; and lower drive, fun, and sensation seeking were related to a greater physiological response to the manipulation. Multivariate analyses revealed lower optimism and behavioural drive to be predictive of responding to the placebo manipulation.

Conclusion

Findings are in contrast with prior work in pain paradigms which found higher levels of the same traits to be related to greater placebo analgesic responses. A cluster of traits characterised by behavioural drive, extraversion, optimism and novelty or fun seeking appears to be germane to placebo responsiveness, but contextual stimuli may generate different patterns of responding. A new conceptualisation of placebo responsiveness may be useful. Rather than a ‘placebo personality’ it may be that responsiveness is better typified by a two faceted transactional model, in which different personality facets respond to different contextual contingencies.