Detecting outlying studies in meta-regression models using a forward search algorithm.

When considering data from many trials, it is likely that some of them present a markedly different intervention effect or exert an undue influence on the summary results. We develop a forward search algorithm for identifying outlying and influential studies in meta-analysis models. The forward search algorithm starts by fitting the hypothesized model to a small subset of likely outlier-free studies and proceeds by adding studies into the set one-by-one that are determined to be closest to the fitted model of the existing set. As each study is added to the set, plots of estimated parameters and measures of fit are monitored to identify outliers by sharp changes in the forward plots. We apply the proposed outlier detection method to two real data sets; a meta-analysis of 26 studies that examines the effect of writing-to-learn interventions on academic achievement adjusting for three possible effect modifiers, and a meta-analysis of 70 studies that compares a fluoride toothpaste treatment to placebo for preventing dental caries in children. A simple simulated example is used to illustrate the steps of the proposed methodology, and a small-scale simulation study is conducted to evaluate the performance of the proposed method. Copyright © 2016 John Wiley & Sons, Ltd.

Regression of coronary atherosclerosis: Current evidence and future perspectives

Coronary atherosclerosis has been considered a chronic disease characterized by ongoing progression in response to systemic risk factors and local pro-atherogenic stimuli. As our understanding of the pathobiological mechanisms implicated in atherogenesis and plaque progression is evolving, effective treatment strategies have been developed that led to substantial reduction of the clinical manifestations and acute complications of coronary atherosclerotic disease. More recently, intracoronary imaging modalities have enabled detailed in vivo quantification and characterization of coronary atherosclerotic plaque, serial evaluation of atherosclerotic changes over time, and assessment of vascular responses to effective anti-atherosclerotic medications. The use of intracoronary imaging modalities has demonstrated that intensive lipid lowering can halt plaque progression and may even result in regression of coronary atheroma when the highest doses of the most potent statins are used. While current evidence indicates the feasibility of atheroma regression and of reversal of presumed high-risk plaque characteristics in response to intensive anti-atherosclerotic therapies, these changes of plaque size and composition are modest and their clinical implications remain largely elusive. Growing interest has focused on achieving more pronounced regression of coronary plaque using novel anti-atherosclerotic medications, and more importantly on elucidating ways toward clinical translation of favorable changes of plaque anatomy into more favorable clinical outcomes for our patients.

Systematic analysis of factors associated with progression and regression of ulcerative colitis in 918 patients.

BACKGROUND Studies that systematically assess change in ulcerative colitis (UC) extent over time in adult patients are scarce. AIM To assess changes in disease extent over time and to evaluate clinical parameters associated with this change. METHODS Data from the Swiss IBD cohort study were analysed. We used logistic regression modelling to identify factors associated with a change in disease extent. RESULTS A total of 918 UC patients (45.3% females) were included. At diagnosis, UC patients presented with the following disease extent: proctitis [199 patients (21.7%)], left-sided colitis [338 patients (36.8%)] and extensive colitis/pancolitis [381 (41.5%)]. During a median disease duration of 9 [4-16] years, progression and regression was documented in 145 patients (15.8%) and 149 patients (16.2%) respectively. In addition, 624 patients (68.0%) had a stable disease extent. The following factors were identified to be associated with disease progression: treatment with systemic glucocorticoids [odds ratio (OR) 1.704, P = 0.025] and calcineurin inhibitors (OR: 2.716, P = 0.005). No specific factors were found to be associated with disease regression. CONCLUSIONS Over a median disease duration of 9 [4-16] years, about two-thirds of UC patients maintained the initial disease extent; the remaining one-third had experienced either progression or regression of the disease extent.

Diffusion-weighted imaging in musculoskeletal radiology-clinical applications and future directions

Diffusion-weighted imaging (DWI) is an established diagnostic tool with regards to the central nervous system (CNS) and research into its application in the musculoskeletal system has been growing. It has been shown that DWI has utility in differentiating vertebral compression fractures from malignant ones, assessing partial and complete tears of the anterior cruciate ligament (ACL), monitoring tumor response to therapy, and characterization of soft-tissue and bone tumors. DWI is however less useful in differentiating malignant vs. infectious processes. As of yet, no definitive qualitative or quantitative properties have been established due to reasons ranging from variability in acquisition protocols to overlapping imaging characteristics. Even with these limitations, DWI can still provide clinically useful information, increasing diagnostic accuracy and improving patient management when magnetic resonance imaging (MRI) findings are inconclusive. The purpose of this article is to summarize recent research into DWI applications in the musculoskeletal system.

Simultaneous multi-slice readout-segmented echo planar imaging for accelerated diffusion-weighted imaging of the breast

OBJECTIVES Readout-segmented echo planar imaging (rs-EPI) significantly reduces susceptibility artifacts in diffusion-weighted imaging (DWI) of the breast compared to single-shot EPI but is limited by longer scan times. To compensate for this, we tested a new simultaneous multi-slice (SMS) acquisition for accelerated rs-EPI. MATERIALS AND METHODS After approval by the local ethics committee, eight healthy female volunteers (age, 38.9±13.1 years) underwent breast MRI at 3T. Conventional as well as two-fold (2× SMS) and three-fold (3× SMS) slice-accelerated rs-EPI sequences were acquired at b-values of 50 and 800s/mm(2). Two independent readers analyzed the apparent diffusion coefficient (ADC) in fibroglandular breast parenchyma. The signal-to-noise ratio (SNR) was estimated based on the subtraction method. ADC and SNR were compared between sequences by using the Friedman test. RESULTS The acquisition time was 4:21min for conventional rs-EPI, 2:35min for 2× SMS rs-EPI and 1:44min for 3× SMS rs-EPI. ADC values were similar in all sequences (mean values 1.62×10(-3)mm(2)/s, p=0.99). Mean SNR was 27.7-29.6, and no significant differences were found among the sequences (p=0.83). CONCLUSION SMS rs-EPI yields similar ADC values and SNR compared to conventional rs-EPI at markedly reduced scan time. Thus, SMS excitation increases the clinical applicability of rs-EPI for DWI of the breast.

Owner-perceived, weighted quality-of-life assessments in dogs with spinal cord injuries.

OBJECTIVE To evaluate changes over time in owner-perceived, weighted quality-of-life assessments in dogs with spinal cord injuries and determine whether scores were associated with underlying etiology or with veterinarian-assigned scores for severity of neurologic dysfunction. DESIGN Cohort study. ANIMALS 100 dogs with spinal cord injury. PROCEDURES Duration of dysfunction, modified Frankel neurologic injury score, and etiology were recorded. At initial and recheck (4- to 6-week) evaluations, owners were asked to identify 5 areas or activities they believed had the most influence on their dogs' quality of life, assess their dogs' current status in each area, and provide a weighting for the importance of each area; results were used to construct a weighted quality-of-life score. Owners were also asked to provide a quality-of-life score with a visual analog scale (VAS). RESULTS At initial and recheck evaluations, weighted quality-of-life scores were higher for ambulatory than for nonambulatory dogs. However, scores did not differ among groups when dogs were grouped on the basis of underlying etiology or duration of injury. Dogs with an increase in Frankel score between the initial and recheck evaluations had a significant increase in weighted quality-of-life score, whereas for dogs that did not have any change in Frankel score, initial and recheck weighted quality-of-life scores were not significantly different. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that owner-assigned, weighted quality-of-life scores for dogs with spinal cord injuries did not vary significantly on the basis of underlying etiology or duration of injury but were higher for ambulatory than for nonambulatory dogs.

Evaluation of a questionnaire for obtaining owner-perceived, weighted quality-of-life assessments for dogs with spinal cord injuries.

OBJECTIVE To evaluate a questionnaire for obtaining owner-perceived, weighted quality-oflife assessments for dogs with spinal cord injuries. DESIGN Evaluation study. Animals-100 dogs with spinal cord injuries and 48 healthy control dogs. PROCEDURES The questionnaire was adapted from a questionnaire (the schedule for the evaluation of individual quality of life-direct weighting) used for human patients. Specifically, owners were asked to identify 5 areas or activities they believed had the most influence on their dogs' quality of life, assess their dogs' current status in each of those areas, and provide a weighting for the importance of each area. Results were used to construct a weighted quality-of-life score ranging from 0 to 100 for each dog. Owners were also asked to provide a quality-of-life score with a visual analog scale (VAS). RESULTS A good correlation was found between weighted and VAS quality-of-life scores. Dogs with spinal cord injuries had weighted quality-of-life scores that were significantly lower than scores for control dogs. Quality-of-life areas and activities provided by owners of dogs with spinal cord injuries were similar to areas and activities provided by owners of healthy control dogs and could mostly be encompassed by 5 broader domains: mobility, play or mental stimulation, health, companionship, and other. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the questionnaire could be used to obtain owner-perceived, weighted quality-of-life assessments for dogs with spinal cord injuries. Obtaining owner-perceived quality-of-life assessments for individual dogs should allow veterinarians to better address quality-of-life concerns and expectations of owners.

Uric Acid and Cardiovascular Events: A Mendelian Randomization Study

Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid-regulating single nucleotide polymorphisms. Causal odds ratios and causal hazard ratios (HRs) were calculated using a two-stage regression estimate with the GRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death.

Standard genotyping overestimates transmission of Mycobacterium tuberculosis among immigrants in a low incidence country.

Immigrants from high tuberculosis (TB) incidence regions are a risk group for TB in low-incidence countries such as Switzerland. In a previous analysis of a nationwide collection of 520 Mycobacterium tuberculosis isolates from 2000-2008, we identified 35 clusters comprising 90 patients based on standard genotyping (24-loci MIRU-VNTR and spoligotyping). Here, we used whole genome sequencing (WGS) to revisit these transmission clusters. Genome-based transmission clusters were defined as isolate pairs separated by ≤12 single nucleotide polymorphisms (SNPs). WGS confirmed 17/35 (49%) MIRU-VNTR clusters; the other 18 clusters contained pairs separated by >12 SNPs. Most transmission clusters (3/4) of Swiss-born patients were confirmed by WGS, as opposed to 25% (4/16) of clusters involving only foreign-born patients. The overall clustering proportion using standard genotyping was 17% (90 patients, 95% confidence interval [CI]: 14-21%), but only 8% (43 patients, 95% CI: 6-11%) using WGS. The clustering proportion was 17% (67/401, 95% CI: 13-21%) using standard genotyping and 7% (26/401, 95% CI: 4-9%) using WGS among foreign-born patients, and 19% (23/119, 95% CI: 13-28%) and 14% (17/119, 95% CI: 9-22%), respectively, among Swiss-born patients. Using weighted logistic regression, we found weak evidence for an association between birth origin and transmission (aOR 2.2, 95% CI: 0.9-5.5, comparing Swiss-born patients to others). In conclusion, standard genotyping overestimated recent TB transmission in Switzerland when compared to WGS, particularly among immigrants from high TB incidence regions, where genetically closely related strains often predominate. We recommend the use of WGS to identify transmission clusters in low TB incidence settings.

An intercontinental comparison of chironomid palaeotemperature inference models: Europe vs North America

Chironomid-temperature inference models based on North American, European and combined surface sediment training sets were compared to assess the overall reliability of their predictions. Between 67 and 76 of the major chironomid taxa in each data set showed a unimodal response to July temperature, whereas between 5 and 22 of the common taxa showed a sigmoidal response. July temperature optima were highly correlated among the training sets, but the correlations for other taxon parameters such as tolerances and weighted averaging partial least squares (WA-PLS) and partial least squares (PLS) regression coefficients were much weaker. PLS, weighted averaging, WA-PLS, and the Modern Analogue Technique, all provided useful and reliable temperature inferences. Although jack-knifed error statistics suggested that two-component WA-PLS models had the highest predictive power, intercontinental tests suggested that other inference models performed better. The various models were able to provide good July temperature inferences, even where neither good nor close modern analogues for the fossil chironomid assemblages existed. When the models were applied to fossil Lateglacial assemblages from North America and Europe, the inferred rates and magnitude of July temperature changes varied among models. All models, however, revealed similar patterns of Lateglacial temperature change. Depending on the model used, the inferred Younger Dryas July temperature decrease ranged between 2.5 and 6°C.

ALTERATIONS IN HYPOTHALAMIC CONTENT OF LUTEINIZING HORMONE RELEASING HORMONE AND PITUITARY RESPONSIVENESS ASSOCIATED WITH TESTICULAR REGRESSION INDUCED BY PINEAL RELATED TREATMENTS IN THE GOLDEN HAMSTER

The adult male golden hamster, when exposed to blinding (BL), short photoperiod (SP), or daily melatonin injections (MEL) demonstrates dramatic reproductive collapse. This collapse can be blocked by removal of the pineal gland prior to treatment. Reproductive collapse is characterized by a dramatic decrease in both testicular weight and serum gonadotropin titers. The present study was designed to examine the interactions of the hypothalamus and pituitary gland during testicular regression, and to specifically compare and contrast changes caused by the three commonly employed methods of inducing testicular regression (BL,SP,MEL). Hypothalamic LHRH content was altered by all three treatments. There was an initial increase in content of LHRH that occurred concomitantly with the decreased serum gonadotropin titers, followed by a precipitous decline in LHRH content which reflected the rapid increases in both serum LH and FSH which occur during spontaneous testicular recrudescence. In vitro pituitary responsiveness was altered by all three treatments: there was a decline in basal and maximally stimulatable release of both LH and FSH which paralleled the fall of serum gonadotropins. During recrudescence both basal and maximal release dramatically increased in a manner comparable to serum hormone levels. While all three treatments were equally effective in their ability to induce changes at all levels of the endocrine system, there were important temporal differences in the effects of the various treatments. Melatonin injections induced the most rapid changes in endocrine parameters, followed by exposure to short photoperiod. Blinding required the most time to induce the same changes. This study has demonstrated that pineal-mediated testicular regression is a process which involves dynamic changes in multiply-dependent endocrine relationships, and proper evaluation of these changes must be performed with specific temporal events in mind. ^

Efficiency Bounds for Estimating Linear Functionals of Nonparametric Regression Models with Endogenous Regressors

Consider a nonparametric regression model Y=mu*(X) + e, where the explanatory variables X are endogenous and e satisfies the conditional moment restriction E[e|W]=0 w.p.1 for instrumental variables W. It is well known that in these models the structural parameter mu* is 'ill-posed' in the sense that the function mapping the data to mu* is not continuous. In this paper, we derive the efficiency bounds for estimating linear functionals E[p(X)mu*(X)] and int_{supp(X)}p(x)mu*(x)dx, where p is a known weight function and supp(X) the support of X, without assuming mu* to be well-posed or even identified.

A Bootstrap-Regression Procedure to Capture Unit Specific Effects in Data Envelopment Analysis

The Data Envelopment Analysis (DEA) efficiency score obtained for an individual firm is a point estimate without any confidence interval around it. In recent years, researchers have resorted to bootstrapping in order to generate empirical distributions of efficiency scores. This procedure assumes that all firms have the same probability of getting an efficiency score from any specified interval within the [0,1] range. We propose a bootstrap procedure that empirically generates the conditional distribution of efficiency for each individual firm given systematic factors that influence its efficiency. Instead of resampling directly from the pooled DEA scores, we first regress these scores on a set of explanatory variables not included at the DEA stage and bootstrap the residuals from this regression. These pseudo-efficiency scores incorporate the systematic effects of unit-specific factors along with the contribution of the randomly drawn residual. Data from the U.S. airline industry are utilized in an empirical application.

Logistic regression models for ordinal response: A study of self-efficacy in colorectal cancer screening

The ordinal logistic regression models are used to analyze the dependant variable with multiple outcomes that can be ranked, but have been underutilized. In this study, we describe four logistic regression models for analyzing the ordinal response variable. ^ In this methodological study, the four regression models are proposed. The first model uses the multinomial logistic model. The second is adjacent-category logit model. The third is the proportional odds model and the fourth model is the continuation-ratio model. We illustrate and compare the fit of these models using data from the survey designed by the University of Texas, School of Public Health research project PCCaSO (Promoting Colon Cancer Screening in people 50 and Over), to study the patient’s confidence in the completion colorectal cancer screening (CRCS). ^ The purpose of this study is two fold: first, to provide a synthesized review of models for analyzing data with ordinal response, and second, to evaluate their usefulness in epidemiological research, with particular emphasis on model formulation, interpretation of model coefficients, and their implications. Four ordinal logistic models that are used in this study include (1) Multinomial logistic model, (2) Adjacent-category logistic model [9], (3) Continuation-ratio logistic model [10], (4) Proportional logistic model [11]. We recommend that the analyst performs (1) goodness-of-fit tests, (2) sensitivity analysis by fitting and comparing different models.^