A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints

Publication bias and related bias in meta-analysis is often examined by visually checking for asymmetry in funnel plots of treatment effect against its standard error. Formal statistical tests of funnel plot asymmetry have been proposed, but when applied to binary outcome data these can give false-positive rates that are higher than the nominal level in some situations (large treatment effects, or few events per trial, or all trials of similar sizes). We develop a modified linear regression test for funnel plot asymmetry based on the efficient score and its variance, Fisher's information. The performance of this test is compared to the other proposed tests in simulation analyses based on the characteristics of published controlled trials. When there is little or no between-trial heterogeneity, this modified test has a false-positive rate close to the nominal level while maintaining similar power to the original linear regression test ('Egger' test). When the degree of between-trial heterogeneity is large, none of the tests that have been proposed has uniformly good properties.

Prediction of first coronary events with the Framingham score: a systematic review

BACKGROUND: Uncertainty exists about the performance of the Framingham risk score when applied in different populations. OBJECTIVE: We assessed calibration of the Framingham risk score (ie, relationship between predicted and observed coronary event rates) in US and non-US populations free of cardiovascular disease. METHODS: We reviewed studies that evaluated the performance of the Framingham risk score to predict first coronary events in a validation cohort, as identified by Medline, EMBASE, BIOSIS, and Cochrane library searches (through August 2005). Two reviewers independently assessed 1496 studies for eligibility, extracted data, and performed quality assessment using predefined forms. RESULTS: We included 25 validation cohorts of different population groups (n = 128,000) in our main analysis. Calibration varied over a wide range from under- to overprediction of absolute risk by factors of 0.57 to 2.7. Risk prediction for 7 cohorts (n = 18658) from the United States, Australia, and New Zealand was well calibrated (corresponding figures: 0.87-1.08; for the 5 biggest cohorts). The estimated population risks for first coronary events were strongly associated (goodness of fit: R2 = 0.84) and in good agreement with observed risks (coefficient for predicted risk: beta = 0.84; 95% CI 0.41-1.26). In 18 European cohorts (n = 109499), the corresponding figures indicated close association (R2 = 0.72) but substantial overprediction (beta = 0.58, 95% CI 0.39-0.77). The risk score was well calibrated on the intercept for both population clusters. CONCLUSION: The Framingham score is well calibrated to predict first coronary events in populations from the United States, Australia, and New Zealand. Overestimation of absolute risk in European cohorts requires recalibration procedures.

Hypovolemia contributes to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus

PURPOSE: To investigate whether body sodium content and blood volume contribute to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus. SUBJECTS AND METHODS: Exchangeable sodium, plasma and blood volumes, and catecholamine, renin, and aldosterone levels were assessed in 10 patients with Type II diabetes mellitus who had orthostatic hypotension and control groups of 40 diabetic patients without orthostatic hypotension and 40 normal subjects of similar age and sex. In subgroups, clinical tests of autonomic function and cardiovascular reactivity to norepinephrine and angiotensin II infusions were performed. RESULTS: In diabetic patients with orthostatic hypotension, mean (+/- SD) supine blood pressure was 165/98 +/- 27/12 mm Hg (P <0.05 compared with other groups) and mean upright blood pressure was 90/60 +/- 38/18 mm Hg. Compared with controls, diabetic patients with orthostatic hypotension had a 10% lower blood volume. They also had less exchangeable sodium than patients with diabetes who did not have orthostatic hypotension (P <0.01). Compared with both groups of controls, diabetic patients with orthostatic hypotension had decreased 24-hour urinary norepinephrine excretion and a reduced diastolic blood pressure response to handgrip (P <0.05). Moreover, they displayed reduced products of exchangeable sodium or blood volume and sympathetic function indexes. Cardiovascular pressor reactivity to norepinephrine was enhanced (P <0.01) and beat-to-beat variation decreased (P <0.01) in both groups of diabetic patients. Microvascular complications were more prevalent in the diabetic patients with orthostatic hypotension (90% vs 35%). CONCLUSIONS: Patients who have Type II diabetes mellitus and orthostatic hypotension are hypovolemic and have sympathoadrenal insufficiency; both factors contribute to the pathogenesis of orthostatic hypotension.

Implant Failure Predictors in the Posterior Maxilla: A Retrospective Study of 273 Consecutive Implants

Background: The goal of this study was to retrospectively analyze a cohort of 136 patients who underwent dental implant placement in the posterior maxilla at the University of Connecticut Health Center to assess and identify predictors for implant failure in the posterior maxilla. Methods: Data were retrieved from patient charts to identify subjects older than 21 years of age who received dental implant(s) in the posterior maxilla. Patients without a postoperative baseline radiograph were excluded. A recall radiograph was taken 3 to 6 months after implant placement. If there was no recall radiograph, the subject was contacted for a recall visit that included a clinical evaluation and radiographs to determine the implant status. Based on a univariate screening, variables considered potential implant failure predictors included gender, diabetes, smoking, implant length, implant diameter, membrane use, sinus-elevation technique, and surgical complications. These parameters were further assessed, and a multivariable logistic regression was performed with implant failure as a dependant variable. All tests of significance were evaluated at the 0.05 error level. Results: Two hundred seventy-three implants were placed in the posterior maxilla. Fourteen implants failed (early and late failures combined), resulting in a 94.9% overall survival rate. The survival rates for the sinus-elevation group and native bone group were 92.2% and 96.7%, respectively (P = 0.090). Based on the multivariable analysis, sinus floor-elevation procedures were not associated with increased risk for implant failure (P = 0.702). In contrast, smoking and surgical complications had a statistically significant effect on implant failure; the odds ratios for implant failure were 6.4 (P = 0.025) and 8.2 (P = 0.004), respectively. Conclusion: Sinus-elevation procedures with simultaneous or staged implant placement do not increase the risk for implant failure, whereas smoking and surgical complications markedly increase the risk for implant failure.

The effects of excluding patients from the analysis in randomised controlled trials: meta-epidemiological study

OBJECTIVE: To examine whether excluding patients from the analysis of randomised trials are associated with biased estimates of treatment effects and higher heterogeneity between trials. DESIGN: Meta-epidemiological study based on a collection of meta-analyses of randomised trials. DATA SOURCES: 14 meta-analyses including 167 trials that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patient reported pain as an outcome. METHODS: Effect sizes were calculated from differences in means of pain intensity between groups at the end of follow-up, divided by the pooled standard deviation. Trials were combined by using random effects meta-analysis. Estimates of treatment effects were compared between trials with and trials without exclusions from the analysis, and the impact of restricting meta-analyses to trials without exclusions was assessed. RESULTS: 39 trials (23%) had included all patients in the analysis. In 128 trials (77%) some patients were excluded from the analysis. Effect sizes from trials with exclusions tended to be more beneficial than those from trials without exclusions (difference -0.13, 95% confidence interval -0.29 to 0.04). However, estimates of bias between individual meta-analyses varied considerably (tau(2)=0.07). Tests of interaction between exclusions from the analysis and estimates of treatment effects were positive in five meta-analyses. Stratified analyses indicated that differences in effect sizes between trials with and trials without exclusions were more pronounced in meta-analyses with high between trial heterogeneity, in meta-analyses with large estimated treatment benefits, and in meta-analyses of complementary medicine. Restriction of meta-analyses to trials without exclusions resulted in smaller estimated treatment benefits, larger P values, and considerable decreases in between trial heterogeneity. CONCLUSION: Excluding patients from the analysis in randomised trials often results in biased estimates of treatment effects, but the extent and direction of bias is unpredictable. Results from intention to treat analyses should always be described in reports of randomised trials. In systematic reviews, the influence of exclusions from the analysis on estimated treatment effects should routinely be assessed.

Fixed and Flexible: Coexistence of Obligate and Facultative Migratory Strategies in a Freshwater Fish

Migration is an important event in many animal life histories, but the degree to which individual animals participate in seasonal migrations often varies within populations. The powerful ecological and evolutionary consequences of such partial migration are now well documented, but the underlying mechanisms are still heavily debated. One potential mechanism of partial migration is between-individual variation in body condition, where animals in poor condition cannot pay the costs of migration and hence adopt a resident strategy. However, underlying intrinsic traits may overrule such environmental influence, dictating individual consistency in migratory patterns. Unfortunately, field tests of individual consistency compared to the importance of individual condition on migratory propensity are rare. Here we analyse 6 years of field data on roach migration, gathered by tagging almost 3000 individual fish and monitoring their seasonal migrations over extended periods of time. Our aims were to provide a field test of the role of condition in wild fish for migratory decisions, and also to assess individual consistency in migratory tendency. Our analyses reveal that (1) migratory strategy, in terms of migration/residency, is highly consistent within individuals over time and (2) there is a positive relationship between condition and the probability of migration, but only in individuals that adopt a migratory strategy at some point during their lives. However, life-long residents do not differ in condition to migrants, hence body condition is only a good predictor of migratory tendency in fish with migratory phenotypes and not a more general determinant of migratory tendency for the population. As resident individuals can achieve very high body condition and still remain resident, we suggest that our data provides some of the first field evidence to show that both facultative and obligate strategies can co-exist within populations of migratory animals.

Comparative enzymology of 11beta-hydroxysteroid dehydrogenase type 1 from six species.

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1), catalyzing the intracellular activation of cortisone to cortisol, is currently considered a promising target to treat patients with metabolic syndrome; hence, there is considerable interest in the development of selective inhibitors. For preclinical tests of such inhibitors, the characteristics of 11beta-HSD1 from the commonly used species have to be known. Therefore, we determined differences in substrate affinity and inhibitor effects for 11beta-HSD1 from six species. The differences in catalytic activities with cortisone and 11-dehydrocorticosterone were rather modest. Human, hamster and guinea-pig 11beta-HSD1 displayed the highest catalytic efficiency in the oxoreduction of cortisone, while mouse and rat showed intermediate and dog the lowest activity. Murine 11beta-HSD1 most efficiently reduced 11-dehydrocorticosterone, while the enzyme from dog showed lower activity than those from the other species. 7-ketocholesterol (7KC) was stereospecifically converted to 7beta-hydroxycholesterol by recombinant 11beta-HSD1 from all species analyzed except hamster, which showed a slight preference for the formation of 7alpha-hydroxycholesterol. Importantly, guinea-pig and canine 11beta-HSD1 displayed very low 7-oxoreductase activities. Furthermore, we demonstrate significant species-specific variability in the potency of various 11beta-HSD1 inhibitors, including endogenous compounds, natural chemicals and pharmaceutical compounds. The results suggest significant differences in the three-dimensional organization of the hydrophobic substrate-binding pocket of 11beta-HSD1, and they emphasize that species-specific variability must be considered in the interpretation of results obtained from different animal experiments. The assessment of such differences, by cell-based test systems, may help to choose the appropriate animal for safety and efficacy studies of novel potential drug candidates.

Patterns of motor abilities and technical skills as predictors of success for young elite football players

Sport-motor tests play an important role in football talent selections. However, single tests represent only parts of the complex game performance. The best game performance therefore does not necessarily need to go hand in hand with the best results in all tests of a test battery. Considering the complexity of the game performance appropriately, a holistic perspective together with a person-oriented approach are applied. Thereby, systems consisting of several variables are identified and analysed in a longitudinal study. Following this idea, six sport-motor tests were aggregated into a subsystem. 106 young male elite football players were tested three times (2011, 2012, 2013; Mage, t2011=12.26, SD=0.29). One year later (2014) their performance level was enquired. Data were analysed using the LICUR method, a cluster analytical method. Four patterns were identified, which remained stable at all measuring points. The players frequently show intraindividual and structurally similar patterns over time. At the third measuring point, a pattern occurred out of which the players are significantly more likely to advance to the highest performance level one year later. This pattern appears consistently above average, but does not always show best test performances. The significantly frequent development along structurally stable patterns suggests a predictive validity of the subsystem sport-motor tests between the ages of 12 to 15. Above average, but not necessarily outstanding performances both in the motor abilities as well as in the football specific tests appears to be particularly promising. This finding emphasizes the need of a holistic perspective in the talent selection.

Peak oxygen uptake test in the assessment of growth hormone deficiency.

This study aimed at evaluating a peak oxygen uptake test as a simple diagnostic tool to assess growth-hormone deficiency (GHD) in adults. Based on the findings of multiple growth hormone (GH) samplings after the exercise, a single GH sample taken 15 min postexercise revealed high accuracy in the diagnosis of GHD in the present study. A standardized peak oxygen uptake test may, therefore, provide an accurate alternative to more invasive tests of GHD.

Patterns of motor abilities and technical skills as predictors of success for young elite football players

Sport-motor tests play an important role in football talent selections. However, single tests represent only parts of the complex game performance. The best game performance therefore does not necessarily need to go hand in hand with the best results in all tests of a test battery. Considering the complexity of the game performance appropriately, a holistic perspective together with a person-oriented approach are applied. Thereby, systems consisting of several variables are identified and analysed in a longitudinal study. Following this idea, six sport-motor tests were aggregated into a subsystem. 106 young male elite football players were tested three times (2011, 2012, 2013; Mage, t2011=12.26, SD=0.29). One year later (2014) their performance level was enquired. Data were analysed using the LICUR method, a cluster analytical method. Four patterns were identified, which remained stable at all measuring points. The players frequently show intraindividual and structurally similar patterns over time. At the third measuring point, a pattern occurred out of which the players are significantly more likely to advance to the highest performance level one year later. This pattern appears consistently above average, but does not always show best test performances. The significantly frequent development along structurally stable patterns suggests a predictive validity of the subsystem sport-motor tests between the ages of 12 to 15. Above average, but not necessarily outstanding performances both in the motor abilities as well as in the football specific tests appears to be particularly promising. This finding emphasizes the need of a holistic perspective in the talent selection.

EARLINET: potential operationality of a research network

In the framework of ACTRIS (Aerosols, Clouds, and Trace Gases Research Infrastructure Network) summer 2012 measurement campaign (8 June–17 July 2012), EARLINET organized and performed a controlled exercise of feasibility to demonstrate its potential to perform operational, coordinated measurements and deliver products in near-real time. Eleven lidar stations participated in the exercise which started on 9 July 2012 at 06:00 UT and ended 72 h later on 12 July at 06:00 UT. For the first time, the single calculus chain (SCC) – the common calculus chain developed within EARLINET for the automatic evaluation of lidar data from raw signals up to the final products – was used. All stations sent in real-time measurements of a 1 h duration to the SCC server in a predefined netcdf file format. The pre-processing of the data was performed in real time by the SCC, while the optical processing was performed in near-real time after the exercise ended. 98 and 79 % of the files sent to SCC were successfully pre-processed and processed, respectively. Those percentages are quite large taking into account that no cloud screening was performed on the lidar data. The paper draws present and future SCC users' attention to the most critical parameters of the SCC product configuration and their possible optimal value but also to the limitations inherent to the raw data. The continuous use of SCC direct and derived products in heterogeneous conditions is used to demonstrate two potential applications of EARLINET infrastructure: the monitoring of a Saharan dust intrusion event and the evaluation of two dust transport models. The efforts made to define the measurements protocol and to configure properly the SCC pave the way for applying this protocol for specific applications such as the monitoring of special events, atmospheric modeling, climate research and calibration/validation activities of spaceborne observations.

Effects of subthalamic nucleus stimulation on cognition and mood in Parkinson’s disease (PD)

Objective: To assess the neuropsychological outcome as a safety measure and quality control in patients with subthalamic nucleus (STN) stimulation for PD. Background: Deep brain stimulation (DBS) is considered a relatively safe treatment used in patients with movement disorders. However, neuropsychological alterations have been reported in patients with STN DBS for PD. Cognition and mood are important determinants of quality of life in PD patients and must be assessed for safety control. Methods: Seventeen consecutive patients (8 women) who underwent STN DBS for PD have been assessed before and 4 months after surgery. Besides motor symptoms (UPDRS-III), mood (Beck Depression Inventory, Hamilton Depression Rating Scale) and neuropsychological aspects, mainly executive functions, have been assessed (mini mental state examination, semantic and phonematic verbal fluency, go-no go test, stroop test, trail making test, tests of alertness and attention, digit span, wordlist learning, praxia, Boston naming test, figure drawing, visual perception). Paired t-tests were used for comparisons before and after surgery. Results: Patients were 61.6±7.8 years old at baseline assessment. All surgeries were performed without major adverse events. Motor symptoms ‘‘on’’ medication remained stable whereas they improved in the ‘‘off’’ condition (p<0.001). Mood was not depressed before surgery and remained unchanged at follow-up. All neuropsychological assessment outcome measures remained stable at follow-up with the exception of semantic verbal fluency and wordlist learning. Semantic verbal fluency decreased by 21±16% (p<0.001) and there was a trend to worse phonematic verbal fluency after surgery (p=0.06). Recall of a list of 10 words was worse after surgery only for the third attempt of recall (13%, p<0.005). Conclusions: Verbal fluency decreased in our patients after STN DBS, as previously reported. The procedure was otherwise safe and did not lead to deterioration of mood.

Effects of stereotypic behaviour and chronic mild stress on judgement bias in laboratory mice

Cognitive processes are influenced by underlying affective states, and tests of cognitive bias have recently been developed to assess the valence of affective states in animals. These tests are based on the fact that individuals in a negative affective state interpret ambiguous stimuli more pessimistically than individuals in a more positive state. Using two strains of mice we explored whether unpredictable chronic mild stress (UCMS) can induce a negative judgement bias and whether variation in the expression of stereotypic behaviour is associated with variation in judgement bias. Sixteen female CD-1 and 16 female C57BL/6 mice were trained on a tactile conditional discrimination test with grade of sandpaper as a cue for differential food rewards. Once they had learned the discrimination, half of the mice were subjected to UCMS for three weeks to induce a negative affective state. Although UCMS induced a reduced preference for the higher value reward in the judgement bias test, it did not affect saccharine preference or hypothalamic–pituitary–adrenal (HPA) activity. However, UCMS affected responses to ambiguous (intermediate) cues in the judgement bias test. While control mice showed a graded response to ambiguous cues, UCMS mice of both strains did not discriminate between ambiguous cues and tended to show shorter latencies to the ambiguous cues and the negative reference cue. UCMS also increased bar-mouthing in CD-1, but not in C57BL/6 mice. Furthermore, mice with higher levels of stereotypic behaviour made more optimistic choices in the judgement bias test. However, no such relationship was found for stereotypic bar-mouthing, highlighting the importance of investigating different types of stereotypic behaviour separately.