Global Analysis of Methylation Profiles From High Resolution CpG Data

New high throughput technologies are now enabling simultaneous epigenetic profiling of DNA methylation at hundreds of thousands of CpGs across the genome. A problem of considerable practical interest is identification of large scale, global changes in methylation that are associated with environmental variables, clinical outcomes, or other experimental conditions. However, there has been little statistical research on methods for global methylation analysis using technologies with individual CpG resolution. To address this critical gap in the literature, we develop a new strategy for global analysis of methylation profiles using a functional regression approach wherein we approximate either the density or the cumulative distribution function (CDF) of the methylation values for each individual using B‐spline basis functions. The spline coefficients for each individual are allowed to summarize the individual's overall methylation profile. We then test for association between the overall distribution and a continuous or dichotomous outcome variable using a variance component score test that naturally accommodates the correlation between spline coefficients. Simulations indicate that our proposed approach has desirable power while protecting type I error. The method was applied to detect methylation differences, both genome wide and at LINE1 elements, between the blood samples from rheumatoid arthritis patients and healthy controls and to detect the epigenetic changes of human hepatocarcinogenesis in the context of alcohol abuse and hepatitis C virus infection. A free implementation of our methods in the R language is available in the Global Analysis of Methylation Profiles (GAMP) package at http://research.fhcrc.org/wu/en.html .     

Evaluation of multi‐outcome longitudinal studies

Evaluation of intervention effects on multiple outcomes is a common scenario in clinical studies. In longitudinal studies, such evaluation is a challenge if one wishes to adequately capture simultaneous data behavior. In this situation, a common approach is to analyze each outcome separately. As a result, multiple statistical statements describing the intervention effect need to be reported and an adjustment for multiple testing is necessary. This is typically done by means of the Bonferroni procedure, which does not take into account the correlation between outcomes, thus resulting in overly conservative conclusions. We propose an alternative approach for multiplicity adjustment that incorporates dependence between outcomes, resulting in an appreciably less conservative evaluation. The ability of the proposed method to control the familywise error rate is evaluated in a simulation study, and the applicability of the method is demonstrated in two examples from the literature. Copyright © 2015 John Wiley & Sons, Ltd.     

Flexible selection of a single treatment incorporating short‐term endpoint information in a phase II/III clinical trial

Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short‐term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short‐term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.     

On generalized fixed sequence procedures for controlling the FWER

Testing a sequence of pre‐ordered hypotheses to decide which of these can be rejected or accepted while controlling the familywise error rate (FWER) is of importance in many scientific studies such as clinical trials. In this paper, we first introduce a generalized fixed sequence procedure whose critical values are defined by using a function of the numbers of rejections and acceptances, and which allows follow‐up hypotheses to be tested even if some earlier hypotheses are not rejected. We then construct the least favorable configuration for this generalized fixed sequence procedure and present a sufficient condition for the FWER control under arbitrary dependence. Based on the condition, we develop three new generalized fixed sequence procedures controlling the FWER under arbitrary dependence. We also prove that each generalized fixed sequence procedure can be described as a specific closed testing procedure. Through simulation studies and a clinical trial example, we compare the power performance of these proposed procedures with those of the existing FWER controlling procedures. Finally, when the pairwise joint distributions of the true null p‐values are known, we further improve these procedures by incorporating pairwise correlation information while maintaining the control of the FWER. Copyright © 2015 John Wiley & Sons, Ltd.     

Factors associated with HIV testing among male motorbike taxi drivers in urban Vietnam

Using the Attitude-Skills-Knowledge (ASK) model, this study examined the prevalence of, and factors associated with, human immunodeficiency virus (HIV) testing among male motorbike taxi drivers (MMTDs). In a cross-sectional design, using quantitative approaches, 291 MMTDs were recruited from 135 sites across 13 districts in Hanoi, Vietnam, for a face-to-face interview. Applying the ASK model modified as a central theory, logistic regression was used to identify determinants of HIV testing. Although many MMTDs engaged in multiple risk behaviours for HIV, only 20.6% had been tested for HIV during the past 12 months. The tested model included one factor of the ASK model, HIV prevention knowledge (adjusted odds ratio [AOR] = 4.76; 95% confidence interval [CI] = 2.12–10.7) and five additional factors: being married (AOR = 3.13; 95% CI = 1.25–4.78), preferring sex with men or with both men and women (AOR = 8.72; 95% CI = 1.48–51.5), having lower number of lifetime sex partners (AOR = 0.66; 95% CI = 0.49–0.88), higher number of past year sex partners (AOR = 2.97: 95% CI = 1.21–7.31) and discussing condom use when having sex with partners (AOR = 0.08; 95% CI = 0.01–7.31). This modified ASK model provided better fit than the ASK model, as it explained more variance in HIV testing (47 vs. 29.8%). Recognising factors associated with HIV testing among MMTDs enables us to create suitable public health intervention strategies.     

Self-reported hepatitis A vaccination as a predictor of hepatitis A virus antibody protection in U.S. adults: National Health and Nutrition Examination Survey 2007–2012

ObjectivesTo estimate the predictive value of self-reported hepatitis A vaccine (HepA) receipt for the presence of hepatitis A virus (HAV) antibody (anti-HAV) from either past infection or vaccination, as an indicator of HAV protection.MethodsUsing 2007–2012 National Health and Nutrition Examination Survey data, we assigned participants to 4 groups based on self-reported HepA receipt and anti-HAV results. We compared characteristics across groups and calculated three measures of agreement between self-report and serologic status (anti-HAV): percentage concordance, and positive (PPV) and negative (NPV) predictive values. Using logistic regression we investigated factors associated with agreement between self-reported vaccination status and serological results.ResultsDemographic and other characteristics varied significantly across the 4 groups. Overall agreement between self-reported HepA receipt and serological results was 63.6% (95% confidence interval [CI] 61.9–65.2); PPV and NPV of self-reported vaccination status for serological result were 47.0% (95% CI 44.2–49.8) and 69.4% (95% CI 67.0–71.8), respectively. Mexican American and foreign-born adults had the highest PPVs (71.5% [95% CI 65.9–76.5], and 75.8% [95% CI 71.4–79.7]) and the lowest NPVs (21.8% [95% CI 18.5–25.4], and 20.0% [95% CI 17.2–23.1]), respectively. Young (ages 20–29 years), US-born, and non-Hispanic White adults had the lowest PPVs (37.9% [95% CI 34.5–41.5], 39.1% [95% CI, 36.0–42.3], and 39.8% [36.1–43.7]), and the highest NPVs (76.9% [95% CI 72.2–81.0, 78.5% [95% CI 76.5–80.4)], and 80.6% [95% CI 78.2–82.8), respectively. Multivariate logistic analyses found age, race/ethnicity, education, place of birth and income to be significantly associated with agreement between self-reported vaccination status and serological results.ConclusionsWhen assessing hepatitis A protection, self-report of not having received HepA was most likely to identify persons at risk for hepatitis A infection (no anti-HAV) among young, US-born and non-Hispanic White adults, and self-report of HepA receipt was least likely to be reliable among adults with the same characteristics.     

Env–2dCD4S60C complexes act as super immunogens and elicit potent,broadly neutralizing antibodies against clinically relevant human immunodeficiency virus type 1 (HIV-1)

The ability to induce a broadly neutralizing antibody (bNAb) response following vaccination is regarded as a crucial aspect in developing an effective vaccine against human immunodeficiency virus type 1 (HIV-1). The bNAbs target the HIV-1 envelope glycoprotein (Env) which is exposed on the virus surface, thereby preventing cell entry. To date, conventional vaccine approaches such as the use of Env-based immunogens have been unsuccessful. We expressed, purified, characterized and evaluated the immunogenicity of several unique HIV-1 subtype C Env immunogens in small animals. Here we report that vaccine immunogens based on Env liganded to a two domain CD4 variant, 2dCD4^S60C are capable of consistently eliciting potent, broadly neutralizing antibody responses in New Zealand white rabbits against a panel of clinically relevant HIV-1 pseudoviruses. This was irrespective of the Env protein subtype and context. Importantly, depletion of the anti-CD4 antibodies appeared to abrogate the neutralization activity in the rabbit sera. Taken together, this data suggests that the Env–2dCD4^S60C complexes described here are “super” immunogens, and potentially immunofocus antibody responses to a unique epitope spanning the 2dCD4^60C. Recent data from the two available anti-CD4 monoclonal antibodies, Ibalizumab and CD4-Ig (and bispecific variants thereof) have highlighted that the use of these broad and potent entry inhibitors could circumvent the need for a conventional vaccine targeting HIV-1. Overall, the ability of the unique Env–2dCD4^S60C complexes to elicit potent bNAb responses has not been described previously, reinforcing that further investigation for their utility in preventing and controlling HIV-1/SIV infection is warranted.     

孕妇微生态系统失衡与早产关系的研究

妊娠期微生态对母婴健康至关重要。近年有关孕妇微生物群落失调对早产影响的文献报道有所增加。早产是导致婴幼儿患病和死亡的主要原因,是严重影响孕产妇和胎儿健康的重要不良事件之一,也是导致发达国家与发展中国家孕产妇围生期发病率和病死率增高的主要原因。笔者拟就孕妇微生态系统失衡与早产关系的最新研究进展进行阐述,重点讨论孕妇肠道、胎盘和阴道的微生态与早产的关系,旨在为临床预防早产提供参考。     

Level of evidence for promising subgroup findings: The case of trends and multiple subgroups

Subgroup analyses are an essential part of fully understanding the complete results from confirmatory clinical trials. However, they come with substantial methodological challenges. In case no statistically significant overall treatment effect is found in a clinical trial, this does not necessarily indicate that no patients will benefit from treatment. Subgroup analyses could be conducted to investigate whether a treatment might still be beneficial for particular subgroups of patients. Assessment of the level of evidence associated with such subgroup findings is primordial as it may form the basis for performing a new clinical trial or even drawing the conclusion that a specific patient group could benefit from a new therapy. Previous research addressed the overall type I error and the power associated with a single subgroup finding for continuous outcomes and suitable replication strategies. The current study aims at investigating two scenarios as part of a nonconfirmatory strategy in a trial with dichotomous outcomes: (a) when a covariate of interest is represented by ordered subgroups, eg, in case of biomarkers, and thus, a trend can be studied that may reflect an underlying mechanism, and (b) when multiple covariates, and thus multiple subgroups, are investigated at the same time. Based on simulation studies, this paper assesses the credibility of subgroup findings in overall nonsignificant trials and provides practical recommendations for evaluating the strength of evidence of subgroup findings in these settings.     

广西高校新生对HIV尿液自助采样包的使用意愿及关注因素调查

目的 了解广西高校新生对HIV尿液自助采样包的使用意愿及关注因素,为进一步在高校开展HIV尿液自我采样传递检测提供依据和参考。 方法 采取整群随机抽样方法,分别选取广西A、B两所高校新生进行匿名问卷调查,其中,A校在健康教育讲座前问卷调查,B校在健康教育讲座后问卷调查。 结果 本次调查中,共发放问卷500份,A、B两所高校新生的问卷回收率分别是88.0%(132/150),96.9%(339/350),差异有统计学意义(P<0.001)。A、B两所高校新生艾滋病基本知识平均知晓率分别为73.7%,87.7%,差异有统计学意义(P<0.001)。受访的大学新生中有2.3%(11/471)曾接受过HIV检测。A、B两所高校新生对HIV尿液自助采样包的使用意愿率分别是63.6%(84/132),88.5%(300/339),差异有统计学意义(P<0.001)。男生对HIV尿液自助采样包的使用意愿率均要稍高于女生,但差异无统计学意义(P>0.05)。在阻碍HIV尿液自助采样包的使用因素调查中,54.0%(47/87)认为操作流程不方便,37.9%(33/87)怀疑结果的准确性,8.1%(7/87)认为容易污染。此外,在大学新生对HIV尿液自助采样包的关注因素调查中,首要关注的是保密性(85.4%,402/471),其次是准确性(72.4%,341/471)。超过一半的新生认为100~150元是HIV尿液自助采样包的可接受价格范围,高达97%的新生认为检测结果的反馈时长应小于7 d。 结论 广西高校新生对HIV尿液自助采样包的态度积极,使用意愿较高,对HIV尿液自我采样传递检测持相对开放态度。HIV尿液自助采样包的保密性和准确性是大学新生最为关注的两个因素。举办健康教育讲座对HIV尿液自助采样包进行适当的介绍和宣传,可有效提高使用意愿。