General Design Bayesian Generalized Linear Mixed Models

Linear mixed models are able to handle an extraordinary range of complications in regression-type analyses. Their most common use is to account for within-subject correlation in longitudinal data analysis. They are also the standard vehicle for smoothing spatial count data. However, when treated in full generality, mixed models can also handle spline-type smoothing and closely approximate kriging. This allows for nonparametric regression models (e.g., additive models and varying coefficient models) to be handled within the mixed model framework. The key is to allow the random effects design matrix to have general structure; hence our label general design. For continuous response data, particularly when Gaussianity of the response is reasonably assumed, computation is now quite mature and supported by the R, SAS and S-PLUS packages. Such is not the case for binary and count responses, where generalized linear mixed models (GLMMs) are required, but are hindered by the presence of intractable multivariate integrals. Software known to us supports special cases of the GLMM (e.g., PROC NLMIXED in SAS or glmmML in R) or relies on the sometimes crude Laplace-type approximation of integrals (e.g., the SAS macro glimmix or glmmPQL in R). This paper describes the fitting of general design generalized linear mixed models. A Bayesian approach is taken and Markov chain Monte Carlo (MCMC) is used for estimation and inference. In this generalized setting, MCMC requires sampling from nonstandard distributions. In this article, we demonstrate that the MCMC package WinBUGS facilitates sound fitting of general design Bayesian generalized linear mixed models in practice.Comment: Published at http://dx.doi.org/10.1214/088342306000000015 in the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Self reported aggravating activities do not demonstrate a consistent directional pattern in chronic non specific low back pain patients: An observational study

Question: Do the self-reported aggravating activities of chronic non-specific low back pain patients demonstrate a consistent directional pattern? Design: Cross-sectional observational study. Participants: 240 chronic non specific low back pain patients. Outcome measure: We invited experienced clinicians to classify each of the three self-nominated aggravating activities from the Patient Specific Functional Scale by the direction of lumbar spine movement. Patients were described as demonstrating a directional pattern if all nominated activities moved the spine into the same direction. Analyses were undertaken to determine if the proportion of patients demonstrating a directional pattern was greater than would be expected by chance. Results: In some patients, all tasks did move the spine into the same direction, but this proportion did not differ from chance (p = 0.328). There were no clinical or demographic differences between those who displayed a directional pattern and those who did not (all p > 0.05). Conclusion: Using patient self-reported aggravating activities we were unable to demonstrate the existence of a consistent pattern of adverse movement in patients with chronic non-specific low back pain

A Tutorial of Bland Altman Analysis in A Bayesian Framework

There are two schools of thought in statistical analysis, frequentist, and Bayesian. Though the two approaches produce similar estimations and predictions in large-sample studies, their interpretations are different. Bland Altman analysis is a statistical method that is widely used for comparing two methods of measurement. It was originally proposed under a frequentist framework, and it has not been used under a Bayesian framework despite the growing popularity of Bayesian analysis. It seems that the mathematical and computational complexity narrows access to Bayesian Bland Altman analysis. In this article, we provide a tutorial of Bayesian Bland Altman analysis. One approach we suggest is to address the objective of Bland Altman analysis via the posterior predictive distribution. We can estimate the probability of an acceptable degree of disagreement (fixed a priori) for the difference between two future measurements. To ease mathematical and computational complexity, an interface applet is provided with a guideline

Sequential Data-Adaptive Bandwidth Selection by Cross-Validation for Nonparametric Prediction

We consider the problem of bandwidth selection by cross-validation from a sequential point of view in a nonparametric regression model. Having in mind that in applications one often aims at estimation, prediction and change detection simultaneously, we investigate that approach for sequential kernel smoothers in order to base these tasks on a single statistic. We provide uniform weak laws of large numbers and weak consistency results for the cross-validated bandwidth. Extensions to weakly dependent error terms are discussed as well. The errors may be {\alpha}-mixing or L2-near epoch dependent, which guarantees that the uniform convergence of the cross validation sum and the consistency of the cross-validated bandwidth hold true for a large class of time series. The method is illustrated by analyzing photovoltaic data.Comment: 26 page

Safety and feasibility of transcranial direct current stimulation (tDCS) combined with sensorimotor retraining in chronic low back pain: a protocol for a pilot randomised controlled trial

Introduction Chronic low back pain (LBP) is a common and costly health problem yet current treatments demonstrate at best, small effects. The concurrent application of treatments with synergistic clinical and mechanistic effects may improve outcomes in chronic LBP. This pilot trial aims to (1) determine the feasibility, safety and perceived patient response to a combined transcranial direct current stimulation (tDCS) and sensorimotor retraining intervention in chronic LBP and (2) provide data to support a sample size calculation for a fully powered trial should trends of effectiveness be present. Methods and analysis A pilot randomised, assessor and participant-blind, sham-controlled trial will be conducted. Eighty participants with chronic LBP will be randomly allocated to receive either (1) active tDCS + sensorimotor retraining or (2) sham tDCS + sensorimotor retraining. tDCS (active or sham) will be applied to the primary motor cortex for 20 min immediately prior to 60 min of supervised sensorimotor retraining twice per week for 10 weeks. Participants in both groups will complete home exercises three times per week. Feasibility, safety, pain, disability and pain system function will be assessed immediately before and after the 10-week intervention. Analysis of feasibility and safety will be performed using descriptive statistics. Statistical analyses will be conducted based on intention-to-treat and per protocol and will be used to determine trends for effectiveness. Ethics and dissemination Ethical approval has been gained from the institutional human research ethics committee (H10184). Written informed consent will be provided by all participants. Results from this pilot study will be submitted for publication in peer-reviewed journals. Trial registration number ACTRN1261600062448

Transcutaneous Electrical Nerve Stimulation (TENS) for chronic pain - an overview of Cochrane reviews (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows: To provide an overview of evidence from Cochrane systematic reviews of the effectiveness of TENS to reduce pain in adults with chronic pain (excluding headache or migraine). To provide an overview of evidence from Cochrane systematic reviews of the safety of TENS to reduce pain in adults with chronic pain (excluding headache or migraine). To identify possible sources of inconsistency in the approaches taken to evaluating the evidence related to TENS for chronic pain (excluding headache or migraine) in the Cochrane Library with a view to recommending strategies to improve consistency. To highlight areas of remaining uncertainty regarding the effectiveness of TENS for chronic pain (excluding headache or migraine) with a view to recommending strategies to reduce any uncertainty

The translation, validity and reliability of the German version of the Fremantle Back Awareness Questionnaire

Background: The Fremantle Back Awareness Questionnaire (FreBAQ) claims to assess disrupted self-perception of the back. The aim of this study was to develop a German version of the Fre-BAQ (FreBAQ-G) and assess its test-retest reliability, its known-groups validity and its convergent validity with another purported measure of back perception. Methods: The FreBaQ-G was translated following international guidelines for the transcultural adaptation of questionnaires. Thirty-five patients with non-specific CLBP and 48 healthy participants were recruited. Assessor one administered the FreBAQ-G to each patient with CLBP on two separate days to quantify intra-observer reliability. Assessor two administered the FreBaQ-G to each patient on day 1. The scores were compared to those obtained by assessor one on day 1 to assess inter-observer reliability. Known-groups validity was quantified by comparing the FreBAQ-G score between patients and healthy controls. To assess convergent validity, patient\u27s FreBAQ-G scores were correlated to their two-point discrimination (TPD) scores. Results: Intra- and Inter-observer reliability were both moderate with ICC3.1 = 0.88 (95%CI: 0.77 to 0.94) and 0.89 (95%CI: 0.79 to 0.94), respectively. Intra- and inter-observer limits of agreement (LoA) were 6.2 (95%CI: 5.0±8.1) and 6.0 (4.8±7.8), respectively. The adjusted mean difference between patients and controls was 5.4 (95%CI: 3.0 to 7.8, p\u3c0.01). Patient\u27s FreBAQ-G scores were not associated with TPD thresholds (Pearson\u27s r = -0.05, p = 0.79). Conclusions: The FreBAQ-G demonstrated a degree of reliability and known-groups validity. Interpretation of patient level data should be performed with caution because the LoA were substantial. It did not demonstrate convergent validity against TPD. Floor effects of some items of the FreBAQ-G may have influenced the validity and reliability results. The clinimetric properties of the FreBAQ-G require further investigation as a simple measure of disrupted self-perception of the back before firm recommendations on its use can be made

Non-invasive brain stimulation techniques for chronic pain (Review)

Background: This is an updated version of the original Cochrane Review published in 2010, Issue 9, and last updated in 2014, Issue 4. Non-invasive brain stimulation techniques aim to induce an electrical stimulation of the brain in an attempt to reduce chronic pain by directly altering brain activity. They include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS), transcranial random noise stimulation (tRNS) and reduced impedance non-invasive cortical electrostimulation (RINCE). Objectives: To evaluate the efficacy of non-invasive cortical stimulation techniques in the treatment of chronic pain. Search methods: For this update we searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, LILACS and clinical trials registers from July 2013 to October 2017. Selection criteria: Randomised and quasi-randomised studies of rTMS, CES, tDCS, RINCE and tRNS if they employed a sham stimulation control group, recruited patients over the age of 18 years with pain of three months’ duration or more, and measured pain as an outcome. Outcomes of interest were pain intensity measured using visual analogue scales or numerical rating scales, disability, quality of life and adverse events. Data collection and analysis: Two review authors independently extracted and verified data. Where possible we entered data into meta-analyses, excluding studies judged as high risk of bias. We used the GRADE system to assess the quality of evidence for core comparisons, and created three ’Summary of findings’ tables. Main results: We included an additional 38 trials (involving 1225 randomised participants) in this update, making a total of 94 trials in the review (involving 2983 randomised participants). This update included a total of 42 rTMS studies, 11 CES, 36 tDCS, two RINCE and two tRNS. One study evaluated both rTMS and tDCS. We judged only four studies as low risk of bias across all key criteria. Using the GRADE criteria we judged the quality of evidence for each outcome, and for all comparisons as low or very low; in large part this was due to issues of blinding and of precision. rTMS: Meta-analysis of rTMS studies versus sham for pain intensity at short-term follow-up (0 to \u3c 1 week postintervention), (27 studies, involving 655 participants), demonstrated a small effect with heterogeneity (standardised mean difference (SMD) -0.22, 95% confidence interval (CI) -0.29 to -0.16, low-quality evidence). This equates to a 7% (95% CI 5% to 9%) reduction in pain, or a 0.40 (95% CI 0.53 to 0.32) point reduction on a 0 to 10 pain intensity scale, which does not meet the minimum clinically important difference threshold of 15% or greater. Pre-specified subgroup analyses did not find a difference between low-frequency stimulation (low-quality evidence) and rTMS applied to the prefrontal cortex compared to sham for reducing pain intensity at short-term follow-up (very low-quality evidence). High-frequency stimulation of the motor cortex in single-dose studies was associated with a small short-term reduction in pain intensity at short-term follow-up (low-quality evidence, pooled n = 249, SMD -0.38 95% CI -0.49 to -0.27). This equates to a 12% (95% CI 9% to 16%) reduction in pain, or a 0.77 (95% CI 0.55 to 0.99) point change on a 0 to 10 pain intensity scale, which does not achieve the minimum clinically important difference threshold of 15% or greater. The results from multiple-dose studies were heterogeneous and there was no evidence of an effect in this subgroup (very low-quality evidence). We did not find evidence that rTMS improved disability. Meta-analysis of studies of rTMS versus sham for quality of life (measured using the Fibromyalgia Impact Questionnaire (FIQ) at short-term follow-up demonstrated a positive effect (MD -10.80 95% CI -15.04 to -6.55, low-quality evidence). CES: For CES (five studies, 270 participants) we found no evidence of a difference between active stimulation and sham (SMD -0.24, 95% CI -0.48 to 0.01, low-quality evidence) for pain intensity. We found no evidence relating to the effectiveness of CES on disability. One study (36 participants) of CES versus sham for quality of life (measured using the FIQ) at short-term follow-up demonstrated a positive effect (MD -25.05 95% CI -37.82 to -12.28, very low-quality evidence). tDCS: Analysis of tDCS studies (27 studies, 747 participants) showed heterogeneity and a difference between active and sham stimulation (SMD -0.43 95% CI -0.63 to -0.22, very low-quality evidence) for pain intensity. This equates to a reduction of 0.82 (95% CI 0.42 to 1.2) points, or a percentage change of 17% (95% CI 9% to 25%) of the control group outcome. This point estimate meets our threshold for a minimum clinically important difference, though the lower confidence interval is substantially below that threshold. We found evidence of small study bias in the tDCS analyses. We did not find evidence that tDCS improved disability. Meta-analysis of studies of tDCS versus sham for quality of life (measured using different scales across studies) at short-term follow-up demonstrated a positive effect (SMD 0.66 95% CI 0.21 to 1.11, low-quality evidence). Adverse events: All forms of non-invasive brain stimulation and sham stimulation appear to be frequently associated with minor or transient side effects and there were two reported incidences of seizure, both related to the active rTMS intervention in the included studies. However many studies did not adequately report adverse events. Authors’ conclusions: There is very low-quality evidence that single doses of high-frequency rTMS of the motor cortex and tDCS may have short-term effects on chronic pain and quality of life but multiple sources of bias exist that may have influenced the observed effects. We did not find evidence that low-frequency rTMS, rTMS applied to the dorsolateral prefrontal cortex and CES are effective for reducing pain intensity in chronic pain. The broad conclusions of this review have not changed substantially for this update. There remains a need for substantially larger, rigorously designed studies, particularly of longer courses of stimulation. Future evidence may substantially impact upon the presented results

Evaluation of subcutaneous proleukin (Interleukin-2) in a randomized international trial (ESPRIT): Geographical and gender differences in the baseline characteristics of participants

Background: ESPRIT, is a phase III, open-label, randomized, international clinical trial evaluating the effects of subcutaneous recombinant interleukin-2 (rIL-2) plus antiretroviral therapy (ART) versus ART alone on HIV-disease progression and death in HIV-1-infected individuals with CD4+ T-cells ≥300 cells/μL. Objectives: To describe the baseline characteristics of participants randomized to ESPRIT overall and by geographic location. Method: Baseline characteristics of randomized participants were summarized by region. Results: 4,150 patients were enrolled in ESPRIT from 254 sites in 25 countries. 41%, 27%, 16%, 11%, and 5% were enrolled in Europe, North America, South America, Asia, and Australia, respectively. The median age was 40 years, 81% were men, and 76%, 11%, and 9% were Caucasian, Asian, and African American or African, respectively. 44% of women enrolled (n = 769) were enrolled in Thailand and Argentina. Overall, 55% and 38% of the cohort acquired HIV through male homosexual and heterosexual contact, respectively. 25% had a prior history of AIDS-defining illness; Pneumocystis jirovecii pneumonia, M. tuberculosis, and esophageal candida were most commonly reported. Median nadir and baseline CD4+ T-cell counts were 199 and 458 cells/μL, respectively. 6% and 13% were hepatitis B or C virus coinfected, respectively. Median duration of antiretroviral therapy (ART) was 4.2 years; the longest median duration was in Australia (5.2 years) and the shortest was in Asia (2.3 years). 17%, 13%, and 69% of participants began ART before 1995, between 1996 and 1997, and from 1998 onward, respectively. 86% used ART from two or more ART classes, with 49% using a protease inhibitor-based regimen and 46% using a nonnucleoside reverse transcriptase inhibitor-based regimen. 78% had plasma HIV RNA below detection (<500 cp/mL). Conclusion: ESPRIT has enrolled a diverse population of HIV-infected individuals including large populations of women and patients of African-American/African and Asian ethnicity often underrepresented in HIV research. As a consequence, the results of the study may have wide global applicability

Validation of the Japanese version of the Fremantle Back Awareness Questionnaire in patients with low back pain

Background: There is a growing interest in the role of disturbed body perception in people with persistent pain problems such as chronic low back pain (CLBP). A questionnaire, the Fremantle Back Awareness Questionnaire (FreBAQ), was recently developed as a simple and quick way of assessing disturbed perceptual awareness of the back in people with CLBP and appears to have acceptable psychometric properties. The aim of the present study was to develop a Japanese version of the FreBAQ (FreBAQ-J) and evaluate its psychometric properties in a sample of Japanese people with low back pain (LBP). Methods: Translation of the FreBAQ into Japanese was conducted using a forward-backward method. One hundred participants with LBP completed the resultant FreBAQ-J. A subset of the participants completed the FreBAQ-J again 2 weeks later. Validity was investigated by examining the relationship between the FreBAQ-J and clinical valuables. Rasch analysis was used to assess targeting, category ordering, unidimensionality, person fit, internal consistency, and differential item functioning. Results: The FreBAQ-J was significantly correlated with pain in motion, disability, pain-related catastrophizing, fear of movement, and anxiety symptomatology. The FreBAQ-J had acceptable internal consistency, a minor departure from unidimensionality, and good test-retest reliability, and was functional on the category rating scale. Conclusions: The FreBAQ-J has acceptable psychometric properties and is suitable for use in people with LBP. Participants with high levels of disturbed body perception are well targeted by the scale. The functioning of one item (item 8) was poor. Further study is warranted to confirm if this item should be exclude