Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility

Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional‐UMVUE and contrast it with other estimates, including naïve estimators, the well‐studied unconditional‐UMVUE and the mean and median Whitehead‐adjusted estimators. The conditional‐UMVUE appears to be a very good choice. Copyright © 2008 John Wiley & Sons, Ltd.     

Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur.

A closed femur fracture pain model was developed in the C57BL/6J mouse. One day after fracture, a monoclonal antibody raised against nerve growth factor (anti-NGF) was delivered intraperitoneally and resulted in a reduction in fracture pain-related behaviors of approximately 50%. Anti-NGF therapy did not interfere with bone healing as assessed by mechanical testing and histomorphometric analysis. INTRODUCTION: Current therapies to treat skeletal fracture pain are limited. This is because of the side effect profile of available analgesics and the scarcity of animal models that can be used to understand the mechanisms that drive this pain. Whereas previous studies have shown that mineralized bone, marrow, and periosteum are innervated by sensory and sympathetic fibers, it is not understood how skeletal pain is generated and maintained even in common conditions such as osteoarthritis, low back pain, or fracture. MATERIALS AND METHODS: In this study, we characterized the pain-related behaviors after a closed femur fracture in the C57BL/6J mouse. Additionally, we assessed the effect of a monoclonal antibody that binds to and sequesters nerve growth factor (anti-NGF) on pain-related behaviors and bone healing (mechanical properties and histomorphometric analysis) after fracture. RESULTS: Administration of anti-NGF therapy (10 mg/kg, days 1, 6, and 11 after fracture) resulted in a reduction of fracture pain-related behaviors of approximately 50%. Attenuation of fracture pain was evident as early as 24 h after the initial dosing and remained efficacious throughout the course of fracture pain. Anti-NGF therapy did not modify biomechanical properties of the femur or histomorphometric indices of bone healing. CONCLUSIONS: These findings suggest that therapies that target NGF or its cognate receptor(s) may be effective in attenuating nonmalignant fracture pain without interfering with bone healing.     

Circulating filarial antigen in cats infected with Brugia pahangi is indicative of the presence of adult worms

Using counterimmunoelectrophoresis with rabbit antisera raised against soluble extracts of adult females of Brugia pahangi parasite antigen was detected in the serum of all cats repeatedly infected with B. pahangi. Antigen was never detected in uninfected cats. The antigen was associated with the presence of adult worms. Antigen was detected consistently in a cat that was amicrofilaraemic but at autopsy harboured only two or three adult worms. Conversely, some cats showed slowly declining numbers of microfilariae and, in these, circulating antigen declined before the number of microfilariae. Eventually no antigen was detectable in circulation whereas microfilariae, although in diminishing numbers, were still present. At autopsy no adult worms were found in these cats. Antigen also appeared in several cats before they became microfilaraemic.     

Computer simulation of the occlusal anatomy of the first mandibular molar after varying the determinants of mandibular movement in the CICERO CAD/CAM system

Static and dynamic occlusal interferences often occur in restorations. The CICERO CAD/CAM technique was used to control the occlusal dimensions of all‐ceramic restorations by setting the variables which determine the mandibular contact movements. The anatomy of the occlusal form of the (pre)molar teeth is influenced by the setting of the sagittal and transversal determinants of mandibular contact movements. In this study the variation in occlusal morphology of a high‐ and low‐limit setting of six variables was compared with an averaged setting. The settings (high, low and averaged, respectively) of the mandibular movement: the sagittal condylar (60°, 0°, 30°) and the incisal guide angle (60°, 0°, 30°) as well as the long centric articulation (1·2 mm, 0 mm, 0·6 mm) influence mainly the antero‐posterior direction, whereas the settings of Bennett movement (laterotrusion: 30°, 0°, 15°), Bennett side shift (laterotranslation: 1, 0, 0·5 mm) and the wide centric (lateral intercuspal contact area: 0·6, 0, 0·3 mm) will mainly influence the transversal direction of the mandibular movement. The influence of the variation of settings on ‘dynamic’ crown morphology as compared with the static crown morphology was studied by comparison of mesio‐distal and bucco‐lingual sections at the same occlusal position of the first lower molar design. Furthermore, the amount of material needed for the correction of the ‘static’ crown to avoid interferences in dynamic conditions was calculated. It appeared that most correction was needed for the ipsilateral settings: Bennett side shift (1·0 mm), Bennett movement (30°) and the Sag. Condylar guidance (0°) as well as the Incisal angle (0°), which could be studied in the bucco‐lingual sections. Also the Bennett side shift on the contra‐lateral side influenced the occlusal contour strongly, which could be seen in the mesio‐distal section. It was concluded that simulation of the influence of several types of determinants of mandibular movement on the three‐dimensional occlusal anatomy can be studied using the CICERO‐CAD/CAM technique. The ipsi‐ and contralateral Bennett side shift variation influenced the occlusal anatomy more than other variables.     

用Sauvegrain法测定青春期骨龄准确性的研究

背景：Sauvegrain方法是通过分析肘部X线片来评估骨龄，常用于青春期生长发育最为迅速的两年间的骨龄测定。本文旨在研究该方法的准确性以及在小儿骨科中的应用价值。 方法：Sauvegrmn法主要评估肘部的4个解剖标志点：外髁、肱骨滑车、尺骨鹰嘴突以及桡骨近端骨骺。它是一个27分制的评分系统。对上述结构所得的评分进行合计而得出一个总分，然后使用标准图表确定骨龄。让三位观察者分别利用该方法进行骨龄评估。三位观察者通过分析60个男孩和60个女孩样本左肘部的前后位和侧位X线片来测定骨龄，并将该结果与通过分析左手和腕部后前位X线片的Greulich和Pyle图谱而得出的骨龄结果进行比较。间隔4周后每个观察者再测定骨龄一次。 结果：通过分析肘部X线片的方法测定骨龄更为精确，因为采用该方法测定骨龄可以精确到半岁。根据观察者的评定，Sauvegrain法显示出很好的观察者之间的相关性（r=0．93）和可重复性（r=0．96）。Sauvegrain法与Greulich和Pyle图谱之间有很好的相关性（r=0．85）。然而，一些肘部生长中心显示出一种中间的发育形态，这种形态学不适合Sauvegrain法的评分。这就导致了数据分析时出现误差。我们建议对于这些样本设定中间评分，并且通过修改原始图表而使评分更为精确。 结论：改良的Sauvegrain法简单、可靠而且可重复性高，它补充了Greulich和Pyle图谱的不足。在临床实践中，骨骼成熟度可以通过骨龄、年生长率以及第二性征而得以很准确的评估。因此，当青春期需要进行骨骺或脊柱关节融合术时，这种方法对于确定手术时间具有重要意义。 可信水平：诊断性研究，Ⅱ级，进一步可信度参见作者介绍。     

Peripheral neuropathy and myonecrosis following hyperthermia and radiation therapy for recurrent prostatic cancer: correlation of damage with predicted SAR pattern.

During the past 10 years, numerous phase I-II studies were conducted and provided clinical experience with combined radiation therapy and hyperthermia treatments. Among the rare complications reported in these combined radiation therapy-hyperthermia trials were myonecrosis and peripheral neuropathy which were felt, mainly on a clinical basis, to be caused by local heat damage. Recently, such complications were noted in two patients with recurrent prostatic cancer treated in our department with radiation therapy combined with deep regional hyperthermia delivered by the Sigma-60 applicator of the BSD 2000 hyperthermia system (Salt Lake City, UT, USA). Analysis of the results of three-dimensional modelling of the SAR (specific absorption rate, W/kg) pattern in these patients indicated high SAR at the sites of the complications. Pretreatment three-dimensional modelling or other methods of predicting potential areas of high power deposition may have a role for future hyperthermia treatment planning aiding in the prevention of possible local heat damage and providing improved delivery of heat to the target volume.