BACKGROUND & AIMS: BACKGROUND:Comparability of cholesterol measurement is clinically required and external quality assurance (EQA) programmes are important to verify the trueness of routine methods. METHODS:We developed a gas chromatography-isotope dilution mass spectrometry (GC-IDMS) total cholesterol assay to investigate the cause of a suspected matrix-related negative bias with the Beckman Coulter enzymatic method discovered in an EQA programme. The GC-IDMS method was calibrated with certified reference material and verified against a secondary reference method. Bias between the GC-IDMS and Beckman Coulter methods was estimated according to Clinical and Laboratory Standards Institute (CLSI) protocol EP9-A2 with 40 clinical samples. RESULTS:At clinically important decision levels, no significant bias was demonstrated on patients' samples (all results within a ±3% limit). A matrix effect confined to the EQA material that affected the Beckman Coulter total cholesterol method was confirmed. CONCLUSIONS:The GC-IDMS method is suitable as a higher order total cholesterol method in a routine clinical laboratory. Matrix effects defeat the objectives of EQA schemes by preventing the verification of trueness. Given the importance of obtaining a true cholesterol result without systematic error, we recommend that EQA material without matrix effects should be used.

背景与目标：

BACKGROUND & AIMS: :SPM is a powerful technique for the comparison of functional imaging data sets among groups of patients. While this technique has been widely applied in studies of adults, it has rarely been applied to studies of children, due in part to the lack of validation of the spatial normalization procedure in children of different ages. In order to determine if spatial normalization of FDG PET images using SPM96 to an adult template can be successfully applied in children, we applied PET-derived transformation parameters to coregistered MRI images. We then compared contours of spatially normalized MRI images obtained from 13 children with epilepsy (ages 2-14 years, mean 7.6 +/- 3.9 years) with those derived from 17 adult controls (mean age 27.6 +/- 4.5 years). Contours of spatially normalized MRI image volumes derived from the pediatric group were more variable than those obtained from adult controls. The average deviation from the mean adult contour was age-dependent and decreased with age (average deviation (mm) = 2.22 (mm) - 0.021 (mm/year) x years, r = 0.70, P < 0.001). Separate SPM analyses were performed for children less than 6 years (N1 = 6) and for children between 6 and 14 years of age (N2 = 7). SPM analyses performed in both pediatric groups showed significant regions of hypometabolism in locations consistent with their epileptic foci. SPM analyses in the younger group also showed significant artifacts. Therefore, the error associated with spatial normalization of pediatric brains to an adult template in children less than 6 years of age precludes the application of statistical parametric mapping in this age group. Although the error in the spatial normalization procedure for children ages 6 to 14 years is higher than in adults, it appears that this error does not result in artifacts in the SPM analysis. Furthermore, in contrast our previous studies showing large age-related changes in the absolute glucose metabolic rate at puberty, the SPM analysis showed children over 6 years of age appear to display the same pattern of glucose utilization as adults. However, small differences in the pattern of glucose utilization which might occur during late childhood and adolescence may not have been detected due to the sample size.

背景与目标： : SPM是一种强大的技术，用于比较患者组之间的功能成像数据集。尽管该技术已广泛应用于成人研究，但很少应用于儿童研究，部分原因是缺乏对不同年龄儿童的空间标准化程序的验证。为了确定使用SPM96对成人模板的FDG PET图像的空间归一化是否可以成功地应用于儿童，我们将PET衍生的转换参数应用于共登记的MRI图像。然后，我们比较了从13名癫痫儿童 (年龄2-14岁，平均7.6 +/- 3.9岁) 获得的空间标准化MRI图像的轮廓与从17名成人对照 (平均年龄27.6 +/- 4.5岁) 获得的轮廓。从儿科组获得的空间标准化MRI图像体积的轮廓比从成人对照组获得的轮廓更可变。与成人平均轮廓的平均偏差是年龄依赖性的，并且随着年龄的增长而降低 (平均偏差 (mm) = 2.22 (mm) - 0.021 (mm/年) x年，r = 0.70，P <0.001)。对6岁以下的儿童 (N1 = 6) 和6至14岁的儿童 (N2 = 7) 进行了单独的SPM分析。在两个儿科组中进行的SPM分析显示，在与癫痫灶一致的位置上，有明显的低代谢区域。年轻组的SPM分析也显示出明显的伪影。因此，与6岁以下儿童的儿童大脑到成人模板的空间标准化相关的误差排除了统计参数映射在该年龄组中的应用。尽管6至14岁儿童的空间归一化过程中的误差高于成人，但似乎此误差不会导致SPM分析中的伪像。此外，与我们以前的研究显示青春期绝对葡萄糖代谢率的大年龄相关变化相反，SPM分析显示6岁以上的儿童似乎表现出与成年人相同的葡萄糖利用模式。但是，由于样本量的原因，可能未发现儿童后期和青春期可能发生的葡萄糖利用模式的微小差异。

BACKGROUND & AIMS: BACKGROUND:Self-reported physical activity is inaccurate, yet few investigators attempt to adjust for measurement error when estimating risks for health outcomes. We estimated what the association between self-reported physical activity and colorectal cancer risk would be if physical activity had been assessed using accelerometry instead. METHODS:We conducted a validation study in which 235 Australian adults completed a telephone-administered International Physical Activity Questionnaire (IPAQ), and wore an accelerometer (Actigraph GT3X+) for 7 days. Using accelerometer-assessed physical activity as the criterion measure, we calculated validity coefficients and attenuation factors using a structural equation model adjusted for age, sex, education and body mass index. We then used a regression calibration approach to apply the attenuation factors to data from the Melbourne Collaborative Cohort Study (MCCS) to compute bias-adjusted hazard ratios (HR) and 95% confidence intervals (CI). RESULTS:Average daily minutes of physical activity from the short form of the International Physical Activity Questionnaire (IPAQ-short) were substantially higher than accelerometer-measured duration (55 versus 32 min). The validity coefficient (0.32; 95% CI: 0.20, 0.43) and attenuation factor (0.20; 95% CI: 0.12, 0.28) were low. The HRs for colorectal cancer risk for high (75th percentile; 411 min/week) versus low (25th percentile; 62 min/week) levels of self-reported physical activity were 0.95 (95% CI: 0.87, 1.05) before and 0.78 (95% CI: 0.47, 1.28) after bias adjustment. CONCLUSIONS:Over-estimation of physical activity by the IPAQ-short substantially attenuates the association between physical activity and colorectal cancer risk, suggesting that the protective effect of physical activity has been previously underestimated.

背景与目标：

BACKGROUND & AIMS: :Our environment contains regularities distributed in space and time that can be detected by way of statistical learning. This unsupervised learning occurs without intent or awareness, but little is known about how it relates to other types of learning, how it affects perceptual processing, and how quickly it can occur. Here we use fMRI during statistical learning to explore these questions. Participants viewed statistically structured versus unstructured sequences of shapes while performing a task unrelated to the structure. Robust neural responses to statistical structure were observed, and these responses were notable in four ways: First, responses to structure were observed in the striatum and medial temporal lobe, suggesting that statistical learning may be related to other forms of associative learning and relational memory. Second, statistical regularities yielded greater activation in category-specific visual regions (object-selective lateral occipital cortex and word-selective ventral occipito-temporal cortex), demonstrating that these regions are sensitive to information distributed in time. Third, evidence of learning emerged early during familiarization, showing that statistical learning can operate very quickly and with little exposure. Finally, neural signatures of learning were dissociable from subsequent explicit familiarity, suggesting that learning can occur in the absence of awareness. Overall, our findings help elucidate the underlying nature of statistical learning.

背景与目标： : 我们的环境包含在空间和时间上分布的规律性，可以通过统计学习来检测。这种无监督的学习是在没有意图或意识的情况下发生的，但是对于它与其他类型的学习如何相关，它如何影响感知处理以及它发生的速度知之甚少。在这里，我们在统计学习期间使用功能磁共振成像来探索这些问题。参与者在执行与结构无关的任务时，查看了统计上结构化的形状序列和非结构化的形状序列。观察到对统计结构的强大神经反应，并且这些反应在四个方面是显着的: 首先，在纹状体和内侧颞叶中观察到对结构的反应，这表明统计学习可能与其他形式的联想学习和关系记忆有关。其次，统计规律在特定类别的视觉区域 (对象选择性的外侧枕叶皮层和单词选择性的腹枕叶颞叶皮层) 中产生了更大的激活，表明这些区域对时间分布的信息敏感。第三，学习的证据在熟悉过程中很早就出现了，这表明统计学习可以非常快地进行并且几乎没有接触。最后，学习的神经特征与随后的明确熟悉程度是分离的，这表明学习可以在没有意识的情况下进行。总的来说，我们的发现有助于阐明统计学习的基本性质。

BACKGROUND & AIMS: :Periodontal researchers frequently use case-control studies, but information on participation rates and the reasons for participation are often missing in the publications, thus hindering the assessment of the validity of those studies. A nested case-control study based on a well-defined population was used to (i) describe the patterns of participation; (ii) show how some associations can be biased; and (iii) illustrate how inverse probability weights can be applied to reduce bias. Differential subject participation was quantified using the ratio between participation for each level and the overall participation. Possible biased associations were illustrated using the odds ratios found for eligible and participant subjects. Finally, we used the estimated probability that an individual participates in the case-control study conditional on that individual's covariate pattern, as observed in the screening study to attempt bias reduction. Considerable differential participation was observed for selected factors, including age, annual tuitions and fees, parental income, and parental education. The strategy used for adjustment of bias resulted in some degree of bias reduction. These findings challenge the inferential validity of many studies on periodontitis. The design and conduct of these studies should aim to improve subject participation and must consider and minimize this potential source of bias.

背景与目标： : 牙周研究人员经常使用病例对照研究，但是出版物中经常缺少有关参与率和参与原因的信息，因此阻碍了对这些研究有效性的评估。基于明确定义的人群的嵌套病例对照研究用于 (i) 描述参与模式; (ii) 显示某些关联如何产生偏差; (iii) 说明如何应用反向概率权重来减少偏差。使用每个级别的参与与总体参与之间的比率来量化受试者的不同参与。使用合格受试者和参与者受试者的比值比说明了可能的偏倚关联。最后，我们使用了在筛选研究中观察到的以个体的协变量模式为条件的个体参与病例对照研究的估计概率，以尝试减少偏倚。对于选定的因素，包括年龄，年度学费和费用，父母收入和父母教育，观察到相当大的参与程度。用于调整偏差的策略导致一定程度的偏差减少。这些发现挑战了许多牙周炎研究的推论有效性。这些研究的设计和实施应旨在提高受试者的参与度，并且必须考虑并最大程度地减少这种潜在的偏见来源。

BACKGROUND & AIMS: :The HET-MN assay (hen's egg test for micronucleus induction) is different from other in vitro genotoxicity assays in that it includes toxicologically important features such as absorption, distribution, metabolic activation, and excretion of the test compound. As a promising follow-up to complement existing in vitro test batteries for genotoxicity, the HET-MN is currently undergoing a formal validation. To optimize the validation, the present study describes a critical analysis of previously obtained HET-MN data to check the experimental design and to identify the most appropriate statistical procedure to evaluate treatment effects. Six statistical challenges (I-VI) of general relevance were identified, and remedies were provided which can be transferred to similarly designed test methods: a Williams-type trend test is proposed for overdispersed counts (II) by means of a square-root transformation which is robust for small sample sizes (I), variance heterogeneity (III), and possible downturn effects at high doses (IV). Due to near-to-zero or even zero-count data occurring in the negative control (V), a conditional comparison of the treatment groups against the mean of the historical controls (VI) instead of the concurrent control was proposed, which is in accordance with US-FDA recommendations. For the modified Williams-type tests, the power can be estimated depending on the magnitude and shape of the trend, the number of dose groups, and the magnitude of the MN counts in the negative control. The experimental design used previously (i.e. six eggs per dose group, scoring of 1000 cells per egg) was confirmed. The proposed approaches are easily available in the statistical computing environment R, and the corresponding R-codes are provided.

背景与目标： : HET-MN测定 (用于微核诱导的鸡蛋测试) 与其他体外遗传毒性测定的不同之处在于，它包括毒理学上重要的特征，例如吸收，分布，代谢活化和测试化合物的排泄。作为补充现有的体外遗传毒性测试电池的有希望的后续行动，HET-MN目前正在进行正式验证。为了优化验证，本研究描述了对先前获得的het-mn数据的严格分析，以检查实验设计并确定最合适的统计程序来评估治疗效果。确定了六个具有一般相关性的统计挑战 (i-vi)，并提供了可以转移到类似设计的测试方法的补救措施: 通过平方根变换，针对过度分散的计数 (II) 提出了威廉姆斯型趋势检验，该方法对于小样本量 (I)，方差异质性 (III) 以及高剂量下可能的下降效应 (IV) 具有鲁棒性。由于阴性对照 (V) 中出现接近零甚至零计数的数据，因此提出了治疗组与历史对照 (VI) 的平均值的条件比较，而不是并发对照，这是根据US-FDA的建议。对于改良的Williams型测试，可以根据趋势的大小和形状，剂量组的数量以及阴性对照中MN计数的大小来估计功率。确认了先前使用的实验设计 (即每个剂量组六个卵，每个卵1000个细胞的评分)。所提出的方法在统计计算环境R中很容易获得，并提供了相应的R代码。

BACKGROUND & AIMS: BACKGROUND:This study examined the criterion validity of the online Active Australia Survey, using accelerometry as the criterion, and whether self-report bias was related to level of activity, age, sex, education, body mass index and health-related quality of life. METHODS:The online Active Australia Survey was validated against the GENEActiv accelerometer as a direct measure of activity. Participants (n = 344) wore an accelerometer for 7 days, completed the Active Australia Survey, and reported their health and demographic characteristics. A Spearman's rank coefficient examined the association between minutes of moderate-to-vigorous physical activity recorded on the Active Australia Survey and GENEActiv accelerometer. A Bland-Altman plot illustrated self-report bias (the difference between methods). Linear mixed effects modelling was used to examine whether participant factors predicted self-report bias. RESULTS:The association between moderate-to-vigorous physical activity reported on the online Active Australia Survey and accelerometer was significant (rs = .27, p < .001). Participants reported 4 fewer minutes per day on the Active Australia Survey than was recorded by accelerometry (95% limits of agreement -104 - 96 min) but the difference was not significant (t(343) = -1.40, p = .16). Self-report bias was negatively associated with minutes of accelerometer-recorded moderate-to-vigorous physical activity and positively associated with mental health-related quality of life. CONCLUSIONS:The online Active Australia Survey showed limited criterion validity against accelerometry. Self-report bias was related to activity level and mental health-related quality of life. Caution is recommended when interpreting studies using the online Active Australia Survey.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:In self-controlled case series (SCCS), the event should not condition the probability of subsequent exposure. If this assumption is not met, an important bias could take place. The association of hip/femur fracture (HFF) and use of benzodiazepines (BDZ) has a bidirectional causal relationship and can serve as case study to investigate the impact of this methodological issue. OBJECTIVES:To assess the magnitude of bias introduced in a SCCS when HFF conditions the posterior exposure to BDZ and explore ways to correct it. METHODS:Four thousand four hundred fifty cases of HFF who had at least one BZD prescription were selected from the primary care health record database BIFAP. Exposure to BZD was divided into non-use, current, recent, and past use. Conditional Poisson regression was used to estimate incidence rate ratios (IRRs) of HFF among current vs non-use/past, adjusted for age. To investigate possible event-exposure dependence, a pre-exposure time of different lengths (15, 30, and 60 days) was excluded from the reference category to evaluate the IRR. RESULTS:IRR of HHF for current use was 0.79 (0.72-0.86); removing 30 days, IRR was 1.43 (1.31-1.57). Removing 15 days, IRR was 1.29 (1.18-1.41), and removing 60 days, IRR was 1.56 (1.42-1.72). A pre-exposure period up to 182 days was necessary to remove such effect giving an IRR of 1.64 (1.48-1.81). CONCLUSIONS:HFF remarkably conditioned the use of BDZs resulting in seriously biased IRRs when this association was studied through a SCCS design. The use of pre-exposure periods of different lengths helped to correct this error.

背景与目标：

BACKGROUND & AIMS: :To reduce PCR bias derived from a primer mismatch, the effect of the annealing temperature on the product ratio was investigated by denaturing gradient gel electrophoresis analysis of PCR products from a mixture of perfect-match and one-mismatch templates. These templates were generated by PCR from Pediococcus acidilactici for one mismatch and Micrococcus luteus for the perfect match. PCRs showed that the bias was reduced at lower temperatures. An environmental sample was also examined.

背景与目标： : 为了减少源自引物错配的PCR偏差，通过对来自完全匹配和一错配模板的混合物的PCR产物进行变性梯度凝胶电泳分析，研究了退火温度对产物比例的影响。这些模板是通过PCR从酸性小球菌中产生的，以进行一次错配，而黄体微球菌则是完美匹配。PCRs显示，在较低的温度下，偏压降低了。还检查了环境样品。

BACKGROUND & AIMS: :In comparative clinical studies, a common goal is to assess whether an exposure, or intervention, affects the outcome of interest. However, just as important is to understand the mechanism(s) for how the intervention affects outcome. For example, if preoperative anemia was shown to increase the risk of postoperative complications by 15%, it would be important to quantify how much of that effect was due to patients receiving intraoperative transfusions. Mediation analysis attempts to quantify how much, if any, of the effect of an intervention on outcome goes though prespecified mediator, or "mechanism" variable(s), that is, variables sitting on the causal pathway between exposure and outcome. Effects of an exposure on outcome can thus be divided into direct and indirect, or mediated, effects. Mediation is claimed when 2 conditions are true: the exposure affects the mediator and the mediator (adjusting for the exposure) affects the outcome. Understanding how an intervention affects outcome can validate or invalidate one's original hypothesis and also facilitate further research to modify the responsible factors, and thus improve patient outcome. We discuss the proper design and analysis of studies investigating mediation, including the importance of distinguishing mediator variables from confounding variables, the challenge of identifying potential mediators when the exposure is chronic versus acute, and the requirements for claiming mediation. Simple designs are considered, as well as those containing multiple mediators, multiple outcomes, and mixed data types. Methods are illustrated with data collected by the National Surgical Quality Improvement Project (NSQIP) and utilized in a companion paper which assessed the effects of preoperative anemic status on postoperative outcomes.

背景与目标： : 在比较临床研究中，一个共同的目标是评估暴露或干预是否会影响感兴趣的结果。但是，同样重要的是要了解干预如何影响结果的机制。例如，如果术前贫血显示15% 增加术后并发症的风险，那么重要的是量化患者接受术中输血的影响程度。中介分析试图量化干预对结果的影响 (如果有的话) 通过预先指定的中介或 “机制” 变量 (即位于暴露与结果之间的因果途径上的变量) 进行多少。因此，暴露对结果的影响可以分为直接和间接或介导的影响。当两个条件为真时，要求调解: 暴露影响调解人，调解人 (针对暴露进行调整) 影响结果。了解干预如何影响结果可以验证或使一个人的原始假设无效，还可以促进进一步的研究以修改负责因素，从而改善患者的结果。我们讨论了调查中介的研究的正确设计和分析，包括区分中介变量和混杂变量的重要性，在暴露是慢性还是急性时识别潜在中介的挑战以及要求调解的要求。考虑了简单的设计，以及包含多个介体，多个结果和混合数据类型的设计。方法用国家外科质量改进项目 (NSQIP) 收集的数据进行说明，并在一篇同伴论文中使用，该论文评估了术前贫血状态对术后结果的影响。

BACKGROUND & AIMS: :Previous investigators have suggested that screening-related biases may explain associations between postmenopausal hormone use and breast cancer. To investigate these biases, we studied postmenopausal women in the Nurses' Health Study from 1988 to 1994. Hormone use is associated with increased subsequent screening. Among women not screened in the previous 2 years, the probability difference, comparing current hormone users with others, for having mammography in the following 2 years is 19.5%; among women previously screened, the difference is 4.9%. These differences persist after control for other factors. If the increase in screening is causal, screening by mammogram could be intermediate in the causal pathway to breast cancer diagnosis. To deal with this problem, we restrict attention to a subset of the cohort in which the effect of postmenopausal hormone use on screening is small (women previously screened). In this subset, the rate ratio comparing breast cancer rates among current postmenopausal hormone users with others is 1.28. In a sensitivity analysis, the bias could not by itself plausibly account for the associations in our data. Our data provide evidence of an association between postmenopausal hormone use and breast cancer that is not solely the product of a detection bias.

背景与目标： : 先前的研究人员认为，与筛查相关的偏见可能解释了绝经后激素使用与乳腺癌之间的关联。为了调查这些偏见，我们在护士健康研究1988年1994年中研究了绝经后妇女。激素的使用与后续筛查的增加有关。在过去2年中未进行筛查的女性中，将当前的激素使用者与其他人进行比较，在接下来的2年中进行乳房x线检查的概率差异为19.5%; 在先前筛查的女性中，差异为4.9%。在控制了其他因素之后，这些差异仍然存在。如果筛查的增加是有原因的，则通过乳房x线照片进行筛查可能是乳腺癌诊断的因果途径的中间环节。为了解决这个问题，我们将注意力集中在绝经后激素使用对筛查的影响很小的队列中的一个子集 (以前筛查过的女性)。在这个子集中，比较当前绝经后激素使用者与其他人的乳腺癌发病率的比率是1.28的。在敏感性分析中，偏差本身无法合理地解释我们数据中的关联。我们的数据提供了绝经后激素使用与乳腺癌之间关联的证据，而这不仅是检测偏倚的产物。

BACKGROUND & AIMS: :Several biological systems such as the biomechanics of human heart, locomotion, and phyllotaxis of plants present a harmonic behavior because their fractal structure are associated to the golden ratio. The golden ratio (Φ = 1.618033988749…), also known as Phi, golden mean, golden section or divine proportion, is an irrational constant found in various forms in nature and recently has been used in many health areas. However, there is no literature on a specific statistical test to identify the golden ratio structures. To validate the results from each survey, it is necessary that statistical techniques be correctly selected and implemented, and the absence of a test to identify the golden ratio may undermines the scientific papers which have this goal. Since the golden number is a ratio, some tests have been wrongly applied in its identification. The objective of this paper is to present and to evaluate methods for identification of golden ratio. Four tests were evaluated: t-Student with ratio statistic (TR), with delta statistic (TΔ), with difference statistic (TED), and Wilcoxon test with statistic difference (WD). Data simulating different samples sizes (n = 2-200) and variability scenarios were used. The tests were assessed regarding type I error rate and power. For TΔ, type I error rate increased along with sample size and variability, achieving 50% in the scenario of relative standard deviation of 12.5% and 20.0% for line segments of lengths a and b, and sample size equal 200. This test also showed lower power when compared to the others in all scenarios. Similarly, for TR, the type I error rate was sensitive to the increasing in sample size, varying from 5 to 60%. On the other hand, WD and TED were associated to low type I error rates (around 5%) and high power (6.1% for sample size equal 2-100% for sample size equal 200). The TΔ and TR were inadequate to identify the golden ratio, since they did not controlled the type I error rate and/or presented low power, leading to possible erroneous conclusions. Therefore WD and TED, both with statistical of difference, appeared as the most appropriate methods to test golden ratio structures.

背景与目标： : 几种生物系统，例如人类心脏的生物力学，植物的运动和叶序形成了调和行为，因为它们的分形结构与黄金比例有关。黄金比例 (Φ   =   1.618033988749…)，也称为Phi，黄金中庸，黄金分割或神圣比例，是自然界中各种形式的非理性常数，最近已在许多健康领域使用。然而，没有关于确定黄金比例结构的特定统计检验的文献。为了验证每次调查的结果，有必要正确选择和实施统计技术，而缺乏确定黄金比例的测试可能会破坏具有此目标的科学论文。由于黄金数字是一个比率，因此在识别时错误地应用了一些测试。本文的目的是介绍和评估黄金分割率的识别方法。评估了四个测试: 具有比率统计 (TR) 的t学生，具有增量统计 (t Δ)，具有差异统计 (TED) 和具有统计差异 (WD) 的Wilcoxon检验。使用了模拟不同样本大小 (n   =   2-200) 和可变性场景的数据。对测试进行了I型错误率和功率评估。对于t Δ，I型错误率随着样本大小和变异性而增加，在长度为a和b的线段的12.5% 和20.0% 的相对标准偏差的情况下实现了50%，并且样本大小200相等。与所有情况下的其他测试相比，该测试还显示出较低的功率。同样，对于TR，I型错误率对样本量的增加敏感，从5到60% 不等。另一方面，WD和TED与低I型错误率 (约5%) 和高功率 (样本大小等于2-100%，样本大小等于200的6.1%) 相关。T Δ 和TR不足以识别黄金比例，因为它们没有控制I型错误率和/或呈现低功率，从而导致可能的错误结论。因此，WD和TED都具有统计学差异，是测试黄金比例结构的最合适方法。

BACKGROUND & AIMS: BACKGROUND:The identification of cell-free fetal DNA (cffDNA) facilitated non-invasive prenatal screening (NIPS) through analysis of cffDNA in maternal plasma. However, challenges regarding its clinical implementation become apparent. Factors affecting fetal fraction should be clarified to guide its clinical application. RESULTS:A total of 13,661 pregnant subjects with singleton pregnancies who undertook NIPS were included in the study. Relationship of gestational age, maternal BMI, and maternal age with the cffDNA fetal fraction in maternal plasmas for NIPS was investigated. Compared with 13 weeks (12.74%) and 14-18 weeks group (12.73%), the fetal fraction in gestational ages of 19-23 weeks, 24-28 weeks, and more than 29 weeks groups significantly increased to 13.11%, 16.14%, and 21.17%, respectively (P < 0.01). Compared with fetal fraction of 14.54% in the maternal BMI group of < 18.5 kg/m2, the percentage of fetal fraction in the group of 18.5-24.9 kg/m2 (13.37%), 25-29.9 kg/m2 (12.20%), 30-34.9 kg/m2 (11.32%), and 35-39.9 kg/m2 (11.57%) decreased significantly (P < 0.01). Compared with the fetal fraction of 14.38% in the group of 18-24 years old, the fetal fraction in the maternal age group of 25-29 years old group (13.98%) (P < 0.05), 30-34 years old group (13.18%) (P < 0.01), 35-39 years old group (12.34%) (P < 0.01), and ≥ 40 years old (11.90%) group (P < 0.01) decreased significantly. CONCLUSIONS:The percentage of fetal fraction significantly increased with increase of gestational age. Decreased fetal fraction with increasing maternal BMI was found. Maternal age was also negatively related to the fetal fraction.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:The analysis of DNA methylation is a key component in the development of personalized treatment approaches. A common way to measure DNA methylation is the calculation of beta values, which are bounded variables of the form M/(M+U) that are generated by Illumina's 450k BeadChip array. The statistical analysis of beta values is considered to be challenging, as traditional methods for the analysis of bounded variables, such as M-value regression and beta regression, are based on regularity assumptions that are often too strong to adequately describe the distribution of beta values. RESULTS:We develop a statistical model for the analysis of beta values that is derived from a bivariate gamma distribution for the signal intensities M and U. By allowing for possible correlations between M and U, the proposed model explicitly takes into account the data-generating process underlying the calculation of beta values. Using simulated data and a real sample of DNA methylation data from the Heinz Nixdorf Recall cohort study, we demonstrate that the proposed model fits our data significantly better than beta regression and M-value regression. CONCLUSION:The proposed model contributes to an improved identification of associations between beta values and covariates such as clinical variables and lifestyle factors in epigenome-wide association studies. It is as easy to apply to a sample of beta values as beta regression and M-value regression.

背景与目标：

BACKGROUND & AIMS: OBJECTIVES:A number of observational studies have reported that, in patients with chronic obstructive pulmonary disease (COPD), β blockers (BBs) decrease risk of mortality and COPD exacerbations. To address important methodological concerns of these studies, we compared the effectiveness and safety of cardioselective BBs versus non-dihydropyridine calcium channel blockers (non-DHP CCBs) in patients with COPD and acute coronary syndromes (ACS) using a propensity score (PS)-matched, active comparator, new user design. We also assessed for potential unmeasured confounding by examining a short-term COPD hospitalisation outcome. SETTING AND PARTICIPANTS:We identified 22 985 patients with COPD and ACS starting cardioselective BBs or non-DHP CCBs across 5 claims databases from the USA, Italy and Taiwan. PRIMARY AND SECONDARY OUTCOME MEASURES:Stratified Cox regression models were used to estimate HRs for mortality, cardiovascular (CV) hospitalisations and COPD hospitalisations in each database after variable-ratio PS matching. Results were combined with random-effects meta-analyses. RESULTS:Cardioselective BBs were not associated with reduced risk of mortality (HR, 0.90; 95% CI 0.78 to 1.02) or CV hospitalisations (HR, 1.06; 95% CI 0.91 to 1.23), although statistical heterogeneity was observed across databases. In contrast, a consistent, inverse association for COPD hospitalisations was identified across databases (HR, 0.54; 95% CI 0.47 to 0.61), which persisted even within the first 30 days of follow-up (HR, 0.55; 95% CI 0.37 to 0.82). Results were similar across a variety of sensitivity analyses, including PS trimming, high dimensional-PS matching and restricting to high-risk patients. CONCLUSIONS:This multinational study found a large inverse association between cardioselective BBs and short-term COPD hospitalisations. The persistence of this bias despite state-of-the-art pharmacoepidemiologic methods calls into question the ability of claims data to address confounding in studies of BBs in patients with COPD.

背景与目标：