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

Abstract Background Time-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. Methods We 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. Results There 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. Conclusions We 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

Study protocol - A systematic review and meta-analysis of hypothermia in experimental traumatic brain injury: Why have promising animal studies not been replicated in pragmatic clinical trials?

Traumatic brain injury (TBI) is a major cause of death and permanent disability. Systemic hypothermia, a treatment used in TBI for many decades, has recently been found to be associated with neutral or unfavourable clinical outcomes despite apparently promising preclinical research. Systematic review and meta‐analysis is a tool to summarize literature and observe trends in experimental design and quality that underpin its general conclusions. Here we aim to use these techniques to describe the use of hypothermia in animal TBI models, collating data relating to outcome and both study design and quality. From here we intend to observe correlations between features and attempt to explain any discrepancies found between animal and clinical data. This protocol describes the relevant methodology in detail

The Efficacy of Trastuzumab in Animal Models of Breast Cancer:A Systematic Review and Meta-Analysis

BACKGROUND:Breast cancer is the most frequent cancers and is the second leading cause of cancer death among women. Trastuzumab is an effective treatment, the first monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2). To inform the development of other effective treatments we report summary estimates of efficacy of trastuzumab on survival and tumour volume in animal models of breast cancer. METHODS:We searched PubMed and EMBASE systematically to identify publications testing trastuzumab in animal models of breast cancer. Data describing tumour volume, median survival and animal features were extracted and we assessed quality using a 12-item checklist. We analysed the impact of study design and quality and evidence for publication bias. RESULTS:We included data from 83 studies reporting 169 experiments using 2076 mice. Trastuzumab treatment caused a substantial reduction in tumour growth, with tumours in treated animals growing to 32.6% of the volume of tumours in control animals (95%CI 27.8%-38.2%). Median survival was prolonged by a factor of 1.45 (1.30-1.62). Many study design and quality features accounted for between-study heterogeneity and we found evidence suggesting publication bias. CONCLUSION:We have found trastuzumab to be effective in animal breast cancer models across a range of experimental circumstances. However the presence of publication bias and a low prevalence of measures to reduce bias provide a focus for future improvements in preclinical breast cancer research

Segmentation of the mouse fourth deep lumbrical muscle connectome reveals concentric organization of motor units

Connectomic analysis of the nervous system aims to discover and establish principles that underpin normal and abnormal neural connectivity and function. Here we performed image analysis of motor unit connectivity in the fourth deep lumbrical muscle (4DL) of mice, using transgenic expression of fluorescent protein in motor neurones as a morphological reporter. We developed a method that accelerated segmentation of confocal image projections of 4DL motor units, by applying high resolution (63×, 1.4 NA objective) imaging or deconvolution only where either proved necessary, in order to resolve axon crossings that produced ambiguities in the correct assignment of axon terminals to identified motor units imaged at lower optical resolution (40×, 1.3 NA). The 4DL muscles contained between 4 and 9 motor units and motor unit sizes ranged in distribution from 3 to 111 motor nerve terminals per unit. Several structural properties of the motor units were consistent with those reported in other muscles, including suboptimal wiring length and distribution of motor unit size. Surprisingly, however, small motor units were confined to a region of the muscle near the nerve entry point, whereas their larger counterparts were progressively more widely dispersed, suggesting a previously unrecognised form of segregated motor innervation in this muscle. We also found small but significant differences in variance of motor endplate length in motor units, which correlated weakly with their motor unit size. Thus, our connectomic analysis has revealed a pattern of concentric innervation that may perhaps also exist in other, cylindrical muscles that have not previously been thought to show segregated motor unit organisation. This organisation may be the outcome of competition during postnatal development based on intrinsic neuronal differences in synaptic size or synaptic strength that generates a territorial hierarchy in motor unit size and disposition

Cumulative meta-analysis.

<p>Plotting cumulative global efficacy estimate with time shows a steady trend for values to become more conservative with time. Plot size is representative of the number of studies, values for which are included on the right hand side, and error bars represent the 95%CI of the mean.</p

PRISMA flowchart of study selection.

<p>The first search was performed on 4 July 2013, using the terms relating to (breast tumor OR breast cancer) AND (trastuzumab OR Herceptin) (See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158240#pone.0158240.s002" target="_blank">S1 Table</a>). On 18 September 2014, we added three further terms to expand the search with previous names of trastuzumab: (breast tumor OR breast cancer) AND ("rhuMAb HER2" OR "Anti-p185HER2 Monoclonal Antibody" OR "muMAb 4D5”).</p

Stratification by animal and tumour model characteristics.

<p>(A) The specific xenograft model used were associated with a significant proportion of the between-study heterogeneity (χ² = 4416, df = 23, P<0.00385). (B) Overexpression of HER2 in breast cancer tumours was associated with greater efficacy (χ² = 160, df = 1, P<0.00385). (C) A greater reduction in tumour volume was observed with subcutaneous inoculation compared to intramammary route (χ² = 810, df = 2, P<0.00385). (D) There is comorbidity related between-study heterogeneity (χ² = 5130, df = 9, P<0.00385). The more commonly used athymic and SCID mice were associated with lower efficacies. (E) A significant proportion of between-study heterogeneity is accounted for by the tumour volume at treatment initiation, with a smaller treatment effect seen at either extreme (χ² = 1042, df = 6, P<0.00385). The grey bands represent global 95% confidence intervals; diamonds (A) and columns (B-E) represent mean±95% CI and diamond size (A) column width (B-E) a measure of number of comparisons within each stratum; the number of comparisons is included inside the y-axis (A) and at the base of each column (B-E). The solid lines in A, C and E represent the level of neutral treatment effect.</p

Evaluation of study quality and publication bias.

<p>(A) Quality score is associated with between-study heterogeneity tumour volume studies, with a trend for higher quality studies to report smaller effect sizes (χ² = 1373, df = 6, p<0.00385). (B) Randomized studies were associated with smaller tumour volume reductions than non-randomised studies (χ² = 68.1, df = 1, p<0.00385). (C and D) Both funnel plot and Egger regression indicate a presence of publication bias in tumour volume data (t = 8.772, p<0.001). Trim and Fill analysis added 38 ‘missing’ studies, with a sizeable reduction in global efficacy estimate (red plots). (E and F) For survival studies, funnel plot does not show any obvious asymmetry, but Egger regression suggests a publication bias (t = 8.772, p<0.001). The grey bands in A and B represent global 95% confidence intervals; columns represent mean ± 95%CI and column width a measure of number of comparisons within each stratum; the number of comparisons is included at the base of each column. Dotted lines in C and E represent global estimates of efficacy before (grey) and after (red) Trim and fill analysis. Dotted lines in D and F represent 95%CI of the regression. The vertical solid lines in A, C, D and F represent the level of neutral treatment effect.</p

Stratification by trastuzumab treatment characteristics.

<p>Total trastuzumab dose (A. χ² = 723, df = 6, P<0.00385), route of drug delivery (B. χ² = 62, df = 3, P<0.00385), cotreatment with oestradiol (C. χ² = 336, df = 1, P<0.00385) and the choice of control (D. χ² = 956, df = 3, P<0.00385), accounted for significant between-study variability in reduction of tumour volume. The grey band represents global 95% confidence intervals; columns represent mean ± 95% CI and column width a measure of number of comparisons within each stratum; the number of comparisons is included at the base of each column.</p

Data from: A systematic review and meta-analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

Background: The development of therapeutics is often characterized by promising animal research that fails to translate into clinical efficacy; this holds for the development of gene therapy in glioma. We tested the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in experimental glioma. Method: We systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a quality checklist. We calculated median survival ratios and used random effects meta-analysis to estimate efficacy. We explored effects of study design and quality and searched for evidence of publication bias. Results: We identified 193 publications using gene therapy in experimental glioma, including 6,366 animals. Overall, gene therapy improved median survival by a factor of 1.60 (95% CI 1.53–1.67). Study quality was low and the type of gene therapy did not account for differences in outcome. Study design characteristics accounted for a significant proportion of between-study heterogeneity. We observed similar findings in a data subset limited to the most common gene therapy. Conclusion: As the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment for glioma. Nevertheless, we have identified areas for improvement in conduct and reporting of studies, and we provide a basis for sample size calculations. Further work should focus on genes of interest in paradigms recapitulating human disease. This might improve the translation of such therapies into the clinic