Direction Of Treatment Effect Research Articles

Strengths of fertilizer and litter effects on seedling recruitment and growth of grassland species differ depending on functional groups and seed size.

Agricultural grasslands play an important role in conserving the biodiversity of the European cultural landscape. Both, litter cover and soil nutrient availability, change with grassland management, but it is not well-studied how seedling recruitment and growth of multiple grassland species are influenced by their single or combined effects. Therefore, we studied the effects of nitrogen fertilization (100 kg N per year and ha) and litter cover (250 gdw per m2) on seedling recruitment and growth of 75 temperate grassland species (16 graminoid species, 51 forb species, 8 legume species) in a full factorial microcosm experiment. Overall, fertilizer reduced seedling emergence, while litter cover increased it even when combined with fertilization. Fertilization increased seedling height and biomass, and the combination of fertilizer and litter resulted in even stronger responses. Litter cover alone did not influence seedling biomass or seedling height. While the overall direction of treatment effects was similar across functional groups, their strengths were mostly weaker in graminoids than in non-legume forbs and legumes. Positive litter effects on seedling emergence were stronger in large-seeded species. Positive fertilization effects on seedling growth were stronger in small-seeded species, while their seedling biomass was negatively affected by litter cover. In summary, our results show for multiple grassland species that the combination of litter cover and fertilization modulates their single effects. The varying sensitivity of how grassland species representing different functional groups and seed sizes respond with their seedling emergence and growth to litter cover and nitrogen fertilization indicates that the consequences of land-use change on grassland diversity and composition already start to manifest in the earliest stages of the plant life cycle.

Using median survival in meta-analysis of experimental time-to-event data

BackgroundTime-to-event data is frequently reported in both clinical and preclinical research spheres. Systematic review and meta-analysis is a tool that can help to identify pitfalls in preclinical research conduct and reporting that can help to improve translational efficacy. However, pooling of studies using hazard ratios (HRs) is cumbersome especially in preclinical meta-analyses including large numbers of small studies. Median survival is a much simpler metric although because of some limitations, which may not apply to preclinical data, it is generally not used in survival meta-analysis. We aimed to appraise its performance when compared with hazard ratio-based meta-analysis when pooling large numbers of small, imprecise studies.MethodsWe simulated a survival dataset with features representative of a typical preclinical survival meta-analysis, including with influence of a treatment and a number of covariates. We calculated individual patient data-based hazard ratios and median survival ratios (MSRs), comparing the summary statistics directly and their performance at random-effects meta-analysis. Finally, we compared their sensitivity to detect associations between treatment and influential covariates at meta-regression.ResultsThere was an imperfect correlation between MSR and HR, although the opposing direction of treatment effects between summary statistics appeared not to be a major issue. Precision was more conservative for HR than MSR, meaning that estimates of heterogeneity were lower. There was a slight sensitivity advantage for MSR at meta-analysis and meta-regression, although power was low in all circumstances.ConclusionsWe believe we have validated MSR as a summary statistic for use in a meta-analysis of small, imprecise experimental survival studies—helping to increase confidence and efficiency in future reviews in this area. While assessment of study precision and therefore weighting is less reliable, MSR appears to perform favourably during meta-analysis. Sensitivity of meta-regression was low for this set of parameters, so pooling of treatments to increase sample size may be required to ensure confidence in preclinical survival meta-regressions.

Abstract 20: Use of Administrative Claims to Ascertain Outcomes in Randomized Clinical Trials for Transcatheter Aortic Valve Replacement: Findings From the Extending Trial-based Evaluations of Medical Therapies Using Novel Sources of Data (EXTEND) Study

Introduction: Administrative claims may be a low cost alternative to traditional clinical trial event adjudication, but whether claims data can validly substitute for adjudicated outcomes to reproduce trial-derived treatment effects is uncertain. Methods: We linked adults aged ≥65 in the US CoreValve Pivotal High Risk (HiR) and Surgical or Transcatheter Aortic Valve Replacement in Intermediate-Risk Patients (SURTAVI) Trials to 100% Medicare inpatient claims (2003-2016). Primary (i.e. death and stroke) and secondary trial endpoints (i.e. bleeding, acute kidney injury, cardiogenic shock, pacemaker implantation, aortic valve reintervention, myocardial infarction, and major adverse cerebrovascular and cardiovascular events [MACCE]) were compared across treatment arms (i.e. TAVR vs. SAVR) using outcomes derived from claims at 1 year (HiR) or 2 years (SURTAVI), and compared with trial-adjudicated outcomes. Results: Among 600 linked HiR participants (linkage rate 80.0%), the rate of the trial’s primary endpoint of all-cause mortality at 1-year was 13.7% for TAVR and 16.4% for SAVR using both trial data (HR 0.84, 95% CI 0.65-1.09; p = 0.33) and claims data (HR 0.86, 95% CI 0.66-1.11; p = 0.34; interaction p-value = 0.80) ( Figure ). Among 1004 linked SURTAVI trial participants (linkage rate 60.5%), the trial’s primary endpoint of combined death and stroke at 2-years was 12.9% for TAVR and 13.1% for SAVR using trial data (HR 1.08, 95% CI 0.79-1.48, p = 0.90), and 11.3% for TAVR and 12.5% for SAVR patients using claims data (HR 1.02, 95% CI 0.73-1.41, p = 0.58; interaction p-value = 0.89) ( Figure ). Procedural secondary outcomes (e.g., aortic valve reintervention, pacemaker implantation) were more concordant between trials and claims than non-procedural outcomes (e.g. bleeding, cardiogenic shock, stroke). Acute kidney injury, myocardial infarction, and MACCE outcomes were also concordant between data types. Conclusions: In both HiR and SURTAVI trials, ascertainment of trial primary endpoints using claims reproduced both the magnitude and direction of treatment effect observed in adjudicated event data. Non-fatal secondary outcomes displayed variable concordance. Use of claims to substitute for adjudicated outcomes in traditional trial treatment comparisons may be a valid alternative for some endpoints.

Individual patient data network meta-analysis using either restricted mean survival time difference or hazard ratios: is there a difference? A case study on locoregionally advanced nasopharyngeal carcinomas

BackgroundThis study aimed at applying the restricted mean survival time difference (rmstD) as an absolute outcome measure in a network meta-analysis and comparing the results with those obtained using hazard ratios (HR) from the individual patient data (IPD) network meta-analysis (NMA) on the role of chemotherapy for nasopharyngeal carcinoma (NPC) recently published by the MAC-NPC collaborative group (Meta-Analysis of Chemotherapy [CT] in NPC).Patients and methodsTwenty trials (5144 patients) comparing radiotherapy (RT) with or without CT in non-metastatic NPC were included. Treatments were grouped in seven categories: RT alone (RT), induction CT followed by RT (IC-RT), RT followed by adjuvant CT (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival and locoregional control. The rmstD was estimated at t* = 10 years in each trial. Random-effect frequentist NMA models were applied. P score was used to rank treatments. Heterogeneity and inconsistency were evaluated.ResultsThe three treatments that had the highest effect on OS with rmstD were CRT-AC, IC-CRT, and CRT (respective P scores of 92%, 72%, and 64%) compared to CRT-AC, CRT, and IC-CRT when using HR (respective P scores of 96%, 71%, and 63%). Of the 32 HR and rmstD analyzed, 5 had a different interpretation, 3 with a direction change (different direction of treatment effect) and 2 with a change in significance (same direction but a change in statistical significance). Results for secondary endpoints were overall in agreement.ConclusionThe use of either HR or rmstD impacts the results of NMA. Given the sensitivity of HR to non-proportional hazards, this finding could have implications in terms of meta-analysis methodology.

Effectiveness of provision of animal-source foods for supporting optimal growth and development in children 6 to 59 months of age.

Effectiveness of provision of animal-source foods for supporting optimal growth and development in children 6 to 59 months of age.

Ambient changes exceed treatment effects on plant species abundance in global change experiments

The responses of species to environmental changes will determine future community composition and ecosystem function. Many syntheses of global change experiments examine the magnitude of treatment effect sizes, but we lack an understanding of how plant responses to treatments compare to ongoing changes in the unmanipulated (ambient or background) system. We used a database of long-term global change studies manipulating CO2 , nutrients, water, and temperature to answer three questions: (a) How do changes in plant species abundance in ambient plots relate to those in treated plots? (b) How does the magnitude of ambient change in species-level abundance over time relate to responsiveness to global change treatments? (c) Does the direction of species-level responses to global change treatments differ from the direction of ambient change? We estimated temporal trends in plant abundance for 791 plant species in ambient and treated plots across 16 long-term global change experiments yielding 2,116 experiment-species-treatment combinations. Surprisingly, for most species (57%) the magnitude of ambient change was greater than the magnitude of treatment effects. However, the direction of ambient change, whether a species was increasing or decreasing in abundance under ambient conditions, had no bearing on the direction of treatment effects. Although ambient communities are inherently dynamic, there is now widespread evidence that anthropogenic drivers are directionally altering plant communities in many ecosystems. Thus, global change treatment effects must be interpreted in the context of plant species trajectories that are likely driven by ongoing environmental changes.

Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer

BackgroundThe hazard ratio (HR) is used routinely to quantify the treatment effect for time-to-event end points in oncology trials, but its use requires that there be proportional hazards in the treatment arms. Non-proportional hazards are observed frequently in cancer immunotherapy trials due to the long-term survival and delayed clinical effect. Although values of HR are quoted in such trials, they are not valid measures of outcome. MethodsReports of parallel group randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors with overall survival data were eligible. For each trial, the ratio of restricted mean survival time (RMST) between the arms was based on reconstructed individual patient data for overall survival. ResultsTwenty-five RCTs totaling 12870 patients were included in this study. Overall survival was used as primary or coprimary end point in 18 trials (72%). In all trials, there was agreement between the ratio of RMST or RMTL and the reported HR about the direction of treatment effect. Estimates of HR provided larger estimates of treatment effect than the ratio of RMST or RMTL in all these trials. The estimated HR and RMST-based measures were in agreement regarding the statistical significance of the effect in all but two trials. ConclusionsRatio of RMST is a complementary technique that provides alternative method of summarizing treatment effects. Proportional hazards of the treatment effect should not be assumed in RCTs evaluating immune checkpoint inhibitors, and RMST analysis should be reported in such trials.

Influence of peer review on the reporting of primary outcome(s) and statistical analyses of randomised trials

BackgroundSelective reporting of outcomes in clinical trials is a serious problem. We aimed to investigate the influence of the peer review process within biomedical journals on reporting of primary outcome(s) and statistical analyses within reports of randomised trials.MethodsEach month, PubMed (May 2014 to April 2015) was searched to identify primary reports of randomised trials published in six high-impact general and 12 high-impact specialty journals. The corresponding author of each trial was invited to complete an online survey asking authors about changes made to their manuscript as part of the peer review process. Our main outcomes were to assess: (1) the nature and extent of changes as part of the peer review process, in relation to reporting of the primary outcome(s) and/or primary statistical analysis; (2) how often authors followed these requests; and (3) whether this was related to specific journal or trial characteristics.ResultsOf 893 corresponding authors who were invited to take part in the online survey 258 (29%) responded. The majority of trials were multicentre (n = 191; 74%); median sample size 325 (IQR 138 to 1010). The primary outcome was clearly defined in 92% (n = 238), of which the direction of treatment effect was statistically significant in 49%. The majority responded (1–10 Likert scale) they were satisfied with the overall handling (mean 8.6, SD 1.5) and quality of peer review (mean 8.5, SD 1.5) of their manuscript. Only 3% (n = 8) said that the editor or peer reviewers had asked them to change or clarify the trial’s primary outcome. However, 27% (n = 69) reported they were asked to change or clarify the statistical analysis of the primary outcome; most had fulfilled the request, the main motivation being to improve the statistical methods (n = 38; 55%) or avoid rejection (n = 30; 44%). Overall, there was little association between authors being asked to make this change and the type of journal, intervention, significance of the primary outcome, or funding source. Thirty-six percent (n = 94) of authors had been asked to include additional analyses that had not been included in the original manuscript; in 77% (n = 72) these were not pre-specified in the protocol. Twenty-three percent (n = 60) had been asked to modify their overall conclusion, usually (n = 53; 88%) to provide a more cautious conclusion.ConclusionOverall, most changes, as a result of the peer review process, resulted in improvements to the published manuscript; there was little evidence of a negative impact in terms of post hoc changes of the primary outcome. However, some suggested changes might be considered inappropriate, such as unplanned additional analyses, and should be discouraged.

Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis.

The role of change in proteinuria as a surrogate end point for randomized trials in immunoglobulin A nephropathy (IgAN) has previously not been thoroughly evaluated. Individual patient-level meta-analysis. Individual-patient data for 830 patients from 11 randomized trials evaluating 4 intervention types (renin-angiotensin system [RAS] blockade, fish oil, immunosuppression, and steroids) examining associations between changes in urine protein and clinical end points at the individual and trial levels. Randomized controlled trials of IgAN with measurements of proteinuria at baseline and a median of 9 (range, 5-12) months follow-up, with at least 1 further year of follow-up for the clinical outcome. 9-month change in proteinuria. Doubling of serum creatinine level, end-stage renal disease, or death. Early decline in proteinuria at 9 months was associated with lower risk for the clinical outcome (HR per 50% reduction in proteinuria, 0.40; 95% CI, 0.32-0.48) and was consistent across studies. Proportions of treatment effect on the clinical outcome explained by early decline in proteinuria were estimated at 11% (95% CI,-19% to 41%) for RAS blockade and 29% (95% CI, 6% to 53%) for steroid therapy. The direction of the pooled treatment effect on early change in proteinuria was in accord with the direction of the treatment effect on the clinical outcome for steroids and RAS blockade. Trial-level analyses estimated that the slope for the regression line for the association of treatment effects on the clinical end points and for the treatment effect on proteinuria was 2.15 (95% Bayesian credible interval, 0.10-4.32). Study population restricted to 11 trials, all having fewer than 200 patients each with a limited number of clinical events. Results of this analysis offer novel evidence supporting the use of an early reduction in proteinuria as a surrogate end point for clinical end points in IgAN in selected settings.

Bridging Qualitative and Quantitative Methods in Organizational Research: Applications of Synthetic Control Methodology in the U.S. Automobile Industry

We assess the utility of synthetic control, a recently developed empirical methodology, for applications in organizational research. Synthetic control acts as a bridge between qualitative and quantitative research methods by enabling researchers to estimate treatment effects in contexts with small samples or few occurrences of a phenomenon or treatment event. The method constructs a counterfactual of a focal firm, or other observational unit, based on an objectively weighted combination of a small number of comparable but untreated firms. By comparing the firm’s actual performance to its counterfactual replica without treatment, synthetic control estimates, under certain assumptions, the magnitude and direction of treatment effects. We illustrate and critique the method in the context of the U.S. auto industry by estimating (a) the effect of government intervention in Chrysler’s management from 2009 to 2011 on its sales volumes and (b) the impact of Toyota’s 2010 “acceleration crisis” on Camry sales.

Model validity and risk of bias in randomised placebo-controlled trials of individualised homeopathic treatment

BackgroundTo date, our programme of systematic reviews has assessed randomised controlled trials (RCTs) of individualised homeopathy separately for risk of bias (RoB) and for model validity of homeopathic treatment (MVHT). ObjectivesThe purpose of the present paper was to bring together our published RoB and MVHT findings and, using an approach based on GRADE methods, to merge the quality appraisals of these same RCTs, examining the impact on meta-analysis results. DesignSystematic review with meta-analysis. MethodsAs previously, 31 papers (reporting a total of 32 RCTs) were eligible for systematic review and were the subject of study. Main outcome measuresFor each trial, the separate ratings for RoB and MVHT were merged to obtain a single overall quality designation (‘high’, ‘moderate, “low”, ‘very low’), based on the GRADE principle of ‘downgrading’. ResultsMerging the assessment of MVHT and RoB identified three trials of ‘high quality’, eight of ‘moderate quality’, 18 of ‘low quality’ and three of ‘very low quality’. There was no association between a trial’s MVHT and its RoB or its direction of treatment effect (P>0.05). The three ‘high quality’ trials were those already labelled ‘reliable evidence’ based on RoB, and so no change was found in meta-analysis based on best-quality evidence: a small, statistically significant, effect favouring homeopathy. ConclusionAccommodating MVHT in overall quality designation of RCTs has not modified our pre-existing conclusion that the medicines prescribed in individualised homeopathy may have small, specific, treatment effects.

Early Change in Proteinuria as a Surrogate End Point for Kidney Disease Progression: An Individual Patient Meta-analysis

It is controversial whether proteinuria is a valid surrogate end point for randomized trials in chronic kidney disease. Meta-analysis of individual patient-level data. Individual patient data for 9,008 patients from 32 randomized trials evaluating 5 intervention types. Randomized controlled trials of kidney disease progression until 2007 with measurements of proteinuria both at baseline and during the first year of follow-up, with at least 1 further year of follow-up for the clinical outcome. Early change in proteinuria. Doubling of serum creatinine level, end-stage renal disease, or death. Early decline in proteinuria was associated with lower risk of the clinical outcome (pooled HR, 0.74 per 50% reduction in proteinuria); this association was stronger at higher levels of baseline proteinuria. Pooled estimates for the proportion of treatment effect on the clinical outcome explained by early decline in proteinuria ranged from-7.0% (95%CI,-40.6% to 26.7%) to 43.9% (95%CI, 25.3% to 62.6%) across 5 intervention types. The direction of the pooled treatment effects on early change in proteinuria agreed with the direction of the treatment effect on the clinical outcome for all 5 intervention types, with the magnitudes of the pooled treatment effects on the 2 end points agreeing for 4 of the 5 intervention types. The pooled treatment effects on both end points were simultaneously stronger at higher levels of proteinuria. However, statistical power was insufficient to determine whether differences in treatment effects on the clinical outcome corresponded to differences in treatment effects on proteinuria between individual studies. Limited variety of interventions tested and low statistical power for many chronic kidney disease clinical trials. These results provide new evidence supporting the use of an early reduction in proteinuria as a surrogate end point, but do not provide sufficient evidence to establish its validity in all settings.

Weighting Components of Composite End Points in Clinical Trials

Conventional analysis of vascular prevention trials assigns equal weight to disparate vascular events in a composite end point at variance with the public's perception of their differential impact on health outcome. This study sought to apply the disability-adjusted life-year (DALY) metric to differential weighting individual vascular end points in trial analyses. DALY values for the most common major end points in vascular prevention trials (nonfatal myocardial infarction, nonfatal stroke, and vascular death), were derived by using World Health Organization Global Burden of Disease Project methodology. The standardized DALYs for each event were applied to recent major primary and secondary vascular prevention trials and to hypothetical model trials. Standardized DALYs lost were 7.63 for nonfatal stroke, 5.14 for nonfatal myocardial infarction, and 11.59 for vascular death. In the published trials analyses, the direction of treatment effects was consistent between DALY and standard event analysis, but the rank order of treatment effect changed for 10 of 18 trials. The DALY analysis also permitted derivation of number-needed-to-treat values to gain 1 DALY: 2.1 for anticoagulation in atrial fibrillation, 2.7 for carotid endarterectomy in symptomatic stenosis, and 4.7 for clopidogrel added to aspirin in acute coronary syndrome. Hypothetical trial analyses demonstrated that the DALY metric more finely discriminates treatment effects. Compared with a nonfatal myocardial infarction, a nonfatal stroke causes a 1.48-fold greater loss and vascular death a 2.25-fold greater loss of DALY. DALY analysis integrates these valuations in a summary metric reflecting the net impact of therapy on patient and societal health, complementing conventional end point analyses.

Interferon beta-1b is effective in Japanese RRMS patients

To assess the efficacy of interferon beta-1b (IFNB-1b) in Japanese patients with relapsing-remitting multiple sclerosis (RRMS). The effects of IFNB in RRMS have been assessed in study populations comprised predominantly of white patients. MS in Japanese patients is different from that in white patients in that there are two different presentations--classic MS (C-MS) and optic-spinal MS (OS-MS)--and chronic progressive forms are infrequent. A total of 205 Japanese patients with RRMS were randomized to receive 50 microg or 250 microg (1.6 or 8.0 MIU) IFNB-1b administered SC every other day for up to 2 years. The primary endpoint was annual relapse rate. Secondary endpoints included further relapse-related and MRI outcome measures, as well as changes in Expanded Disability Status Scale and Neurologic Rating Scale. Efficacy was assessed in 188 patients, and safety was assessed in 192 patients. Supplemental ad hoc subgroup analyses were also performed for patients with OS-MS and those with C-MS. Annual relapse rates were 0.763 in the 250 microg group and 1.069 in the 50 microg group, a relative reduction of 28.6% (p = 0.047). Results for all secondary endpoints favored 250 microg IFNB-1b. Subgroup analyses suggested that the magnitude and direction of treatment effect in patients with OS-MS and C-MS was similar, albeit not significant due to small sample size. Interferon beta-1b (IFNB-1b) 250 microg significantly reduced relapse rates and change in MRI lesion area in Japanese patients with relapsing-remitting multiple sclerosis, and seemed to be comparably effective in optic-spinal multiple sclerosis (MS) and classic MS. The response to treatment with IFNB-1b in Japanese patients with MS suggests that a common pathogenesis and underlying genetic characteristics are shared with white patients.

Therapeutic ultrasound for venous leg ulcers.

Ultrasound therapy is commonly used with the aim of improving the healing of chronic wounds such as pressure ulcers and venous leg ulcers. To assess the effectiveness of therapeutic ultrasound in the treatment of venous leg ulcers. The Cochrane Wounds Group search strategy was used (see Scope) to search for randomised controlled trials (RCTs) of therapeutic ultrasound for the treatment of venous leg ulcers. Randomised controlled trials comparing therapeutic ultrasound with sham ultrasound, or other (standard) treatment Results of searches were scrutinised by one reviewer (and checked by a second) to identify possible RCTs and full reports of these were obtained. Details of eligible studies were extracted and summarised using a data extraction sheet. Attempts were made to obtain missing data by contacting authors. Data extraction was checked by a second reviewer. A total of seven eligible RCTs were identified. Four trials compared ultrasound therapy with sham ultrasound, three trials compared ultrasound therapy with standard treatment. None of the trials found a difference in healing rates between any of the therapies, though it is noteworthy that the direction of treatment effect was consistently in favour of ultrasound (though this did not reach significance in the individual studies). There is no good evidence of a benefit of ultrasound therapy in the healing of venous leg ulcers.

THE GENERALITY OF FIELD EXPERIMENTS: INTERACTIONS BETWEEN LOCAL AND BROAD-SCALE PROCESSES

Linking the results of localized field experiments to generalities about the role of specific processes is essential in ecology. Comparative studies conducted at multiple locations enable the general importance of processes to be assessed. However, spatial or temporal variation in the strength of local ecological relationships frequently makes it difficult to draw general conclusions, as increasing the extent of a study is likely to increase the physical and biological heterogeneity. To unravel the influence of differences in wave climate on local ecological interactions among adult and juvenile sandflat bivalves, an experiment was conducted at three sites in each of three harbors in the North Island of New Zealand. The selected sites covered a range of wind–wave exposures but were all mid-intertidal sandflats with macrobenthic communities dominated by bivalves. Four treatments were used: additions of 0, 15, 45, and 110 adults of the tellinid bivalve Macomona liliana. At each site a DOBIE wave gauge was used to provide time-series data on wave orbital speed at the seabed over the 35-d duration of the experiment. Significant experiment × location interactions indicated site-dependent variation in the strength and direction of treatment effects. However, multiple regression models based on site environmental characteristics were very successful in explaining differences between sites in the strength of experimental treatment effects (66–99% of the variance explained). We used the cube of the orbital wave velocity at the seabed (U3b) as an index of energy dissipation by waves. Both the site average and maximum U3b were important variables explaining location-dependent treatment effects. Average U3b increased the strength of the negative effects of experimental additions of adult Macomona on juvenile bivalves, presumably by increasing the opportunity for juvenile bivalves to be resuspended by small waves and transported away from areas with high adult densities. Maximum U3b decreased the strength of the experimental effects, probably by increasing the purely passive transport of juveniles with sediment bedload and thus obliterating patterns in the distribution of juvenile bivalves relative to adult Macomona. Hence, different aspects of the wave climate influenced adult–juvenile interactions in different ways. Ambient density of adult Macomona around the experimental sites was also an important factor. This multisite experiment confirmed the importance of local adult–juvenile interactions and suggested ways in which these interactions are influenced by local environmental characteristics. Where the influence of such broad-scale variables can be identified, linking broad-scale information to small-scale studies that identify mechanisms can increase the generality of ecological experiments.

Prevention of upper gastrointestinal bleeding from portal hypertension in cirrhosis: rationale for medical treatment.

We updated meta-analysis and critical descriptive analysis of randomized clinical trials (RCTs) assessing the value of beta-blockers in preventing first bleeding (prophylactic) or rebleeding (therapeutic) and on survival of patients with cirrhosis. Both the methods of Peto-Mantel-Haenszel and DerSimonian-Laird were used to assess the heterogeneity and obtain cumulative estimates of treatment effects; the L'Abbé plot was also used for a visual assessment of heterogeneity in the direction of treatment effect. Seven prophylactic and nine therapeutic RCTs were analysed. beta-Blockers uniformly reduced the bleeding risk and revealed a trend toward improved survival in non-ascitic, well-compensated patients in both the prophylactic and therapeutic sets of RCTs. Discordant results were found in patients with ascites or in poor functional condition.

Interferon for non-A, non-B chronic hepatitis

We reviewed randomised clinical trials evaluating the effect of lymphoblastoid or recombinant alpha-interferon in non-A, non-B chronic hepatitis. The outcomes assessed were the rates of serum alanine aminotransferase normalization and relapse during and after stopping interferon. Data were pooled by meta-analysis and a 50% overall rate difference, favouring treated patients, was found. Results showed homogeneity in direction of treatment effect both after short-term (2-6 months, greater than or equal to 2 mega-units thrice weekly) and long-term (9-18 months, variable dose) interferon course. Moreover, results did not change when type of publication (abstracts vs. full reports) and treatment duration or schedule were accounted for. About 50% of patients originally responding to treatment relapsed within 6 months of either dose reduction or stopping interferon, thus suggesting that only in about one out of four patients is benefit from treatment sustained up to 1 year. We conclude that larger trials are needed to identify an optimal schedule of treatment and to evaluate predictors of interferon effectiveness in patients with non-A, non-B chronic hepatitis.

The odds ratio: a useful tool in neurosciences.

The odds ratio is very useful; when used as a measure of association (or to describe the results of a randomised controlled treatment trial) it expresses both the strength and direction of the association (or size and direction of treatment effect). Its 95% confidence interval estimates the likely degree of sampling error and provides a test of significance at the 5% level. Authors, when reporting the results of descriptive studies, case-control studies and randomised controlled trials, should consider presenting their results this way rather than by simple significance testing with a chi squared test.