Anna Falk Delgado

The association of funding source on effect size in randomized controlled trials: 2013–2015 – a cross-sectional survey and meta-analysis

BackgroundTrials financed by for-profit organizations have been associated with favorable outcomes of new treatments, although the effect size of funding source impact on outcome is unknown. The aim of this study was to estimate the effect size for a favorable outcome in randomized controlled trials (RCTs), stratified by funding source, that have been published in general medical journals.MethodsParallel-group RCTs published in The Lancet, New England Journal of Medicine, and JAMA between 2013 and 2015 were identified. RCTs with binary primary endpoints were included. The primary outcome was the OR of patients’ having a favorable outcome in the intervention group compared with the control group. The OR of a favorable outcome in each trial was calculated by the number of positive events that occurred in the intervention and control groups. A meta-analytic technique with random effects model was used to calculate summary OR. Data were stratified by funding source as for-profit, mixed, and nonprofit. Prespecified sensitivity, subgroup, and metaregression analyses were performed.ResultsFive hundred nine trials were included. The OR for a favorable outcome in for-profit-funded RCTs was 1.92 (95% CI 1.72–2.14), which was higher than mixed source-funded RCTs (OR 1.34, 95% CI 1.25–1.43) and nonprofit-funded RCTs (OR 1.32, 95% CI 1.26–1.39). The OR for a favorable outcome was higher for both clinical and surrogate endpoints in for-profit-funded trials than in RCTs with other funding sources. Excluding drug trials lowered the OR for a favorable outcome in for-profit-funded RCTs. The OR for a favorable surrogate outcome in drug trials was higher in for-profit-funded trials than in nonprofit-funded trials.ConclusionsFor-profit-funded RCTs have a higher OR for a favorable outcome than nonprofit- and mixed source-funded RCTs. This difference is associated mainly with the use of surrogate endpoints in for-profit-financed drug trials.

Glioma Grade Discrimination with MR Diffusion Kurtosis Imaging: A Meta-Analysis of Diagnostic Accuracy

Purpose To assess the diagnostic test accuracy and sources of heterogeneity for the discriminative potential of diffusion kurtosis imaging (DKI) to differentiate low-grade glioma (LGG) (World Health Organization [WHO] grade II) from high-grade glioma (HGG) (WHO grade III or IV). Materials and Methods The Cochrane Library, Embase, Medline, and the Web of Science Core Collection were systematically searched by two librarians. Retrieved hits were screened for inclusion and were evaluated with the revised tool for quality assessment for diagnostic accuracy studies (commonly known as QUADAS-2) by two researchers. Statistical analysis comprised a random-effects model with associated heterogeneity analysis for mean differences in mean kurtosis (MK) in patients with LGG or HGG. A bivariate restricted maximum likelihood estimation method was used to describe the summary receiver operating characteristics curve and bivariate meta-regression. Results Ten studies involving 430 patients were included. The mean difference in MK between LGG and HGG was 0.17 (95% confidence interval [CI]: 0.11, 0.22) with a z score equal to 5.86 (P < .001). The statistical heterogeneity was explained by glioma subtype, echo time, and the proportion of recurrent glioma versus primary glioma. The pooled area under the curve was 0.94 for discrimination of HGG from LGG, with 0.85 (95% CI: 0.74, 0.92) sensitivity and 0.92 (95% CI: 0.81, 0.96) specificity. Heterogeneity was driven by neuropathologic subtype and DKI technique. Conclusion MK shows high diagnostic accuracy in the discrimination of LGG from HGG.

Discrimination between Glioma Grades II and III Using Dynamic Susceptibility Perfusion MRI: A Meta-Analysis

BACKGROUND: DSC perfusion has been evaluated in the discrimination between low-grade and high-grade glioma but the diagnostic potential to discriminate beween glioma grades II and III remains unclear. PURPOSE: Our aim was to evaluate the diagnostic accuracy of relative maximal CBV from DSC perfusion MR imaging to discriminate glioma grades II and III. DATA SOURCES: A systematic literature search was performed in PubMed/MEDLINE, Embase, Web of Science, and ClinicalTrials.gov. STUDY SELECTION: Eligible studies reported on patients evaluated with relative maximal CBV derived from DSC with a confirmed neuropathologic diagnosis of glioma World Health Organization grades II and III. Studies reporting on mean or individual patient data were considered for inclusion. DATA ANALYSIS: Data were analyzed by using inverse variance with the random-effects model and receiver operating characteristic curves describing optimal cutoffs and areas under the curve. Bivariate diagnostic random-effects meta-analysis was used to calculate diagnostic accuracy. DATA SYNTHESIS: Twenty-eight studies evaluating 727 individuals were included in the meta-analysis. Individual data were available from 10 studies comprising 190 individuals. The mean difference of relative maximal CBV between glioma grades II and III (n = 727) was 1.76 (95% CI, 1.27–2.24; P < .001). Individual patient data (n = 190) had an area under the curve of 0.77 for discriminating glioma grades II and III at an optimal cutoff of 2.02. When we analyzed astrocytomas separately, the area under the curve increased to 0.86 but decreased to 0.61 when we analyzed oligodendrogliomas. LIMITATIONS: A substantial heterogeneity was found among included studies. CONCLUSIONS: Glioma grade III had higher relative maximal CBV compared with glioma grade II. A high diagnostic accuracy was found for all patients and astrocytomas; however, the diagnostic accuracy was substantially reduced when discriminating oligodendroglioma grades II and III.

Preoperative Quantitative MR Tractography Compared with Visual Tract Evaluation in Patients with Neuropathologically Confirmed Gliomas Grades II and III: A Prospective Cohort Study

Background and Purpose. Low-grade gliomas show infiltrative growth in white matter tracts. Diffusion tensor tractography can noninvasively assess white matter tracts. The aim was to preoperatively assess tumor growth in white matter tracts using quantitative MR tractography (3T). The hypothesis was that suspected infiltrated tracts would have altered diffusional properties in infiltrated tract segments compared to noninfiltrated tracts. Materials and Methods. Forty-eight patients with suspected low-grade glioma were included after written informed consent and underwent preoperative diffusion tensor imaging in this prospective review-board approved study. Major white matter tracts in both hemispheres were tracked, segmented, and visually assessed for tumor involvement in thirty-four patients with gliomas grade II or III (astrocytomas or oligodendrogliomas) on postoperative neuropathological evaluation. Relative fractional anisotropy (rFA) and mean diffusivity (rMD) in tract segments were calculated and compared with visual evaluation and neuropathological diagnosis. Results. Tract segment infiltration on visual evaluation was associated with a lower rFA and high rMD in a majority of evaluated tract segments (89% and 78%, resp.). Grade II and grade III gliomas had similar infiltrating behavior. Conclusion. Quantitative MR tractography corresponds to visual evaluation of suspected tract infiltration. It may be useful for an objective preoperative evaluation of tract segment involvement.

Diffusion kurtosis imaging of gliomas grades II and III - a study of perilesional tumor infiltration, tumor grades and subtypes at clinical presentation

Abstract Background Diffusion kurtosis imaging (DKI) allows for assessment of diffusion influenced by microcellular structures. We analyzed DKI in suspected low-grade gliomas prior to histopathological diagnosis. The aim was to investigate if diffusion parameters in the perilesional normal-appearing white matter (NAWM) differed from contralesional white matter, and to investigate differences between glioma malignancy grades II and III and glioma subtypes (astrocytomas and oligodendrogliomas). Patients and methods Forty-eight patients with suspected low-grade glioma were prospectively recruited to this institutional review board-approved study and investigated with preoperative DKI at 3T after written informed consent. Patients with histologically proven glioma grades II or III were further analyzed (n=35). Regions of interest (ROIs) were delineated on T2FLAIR images and co-registered to diffusion MRI parameter maps. Mean DKI data were compared between perilesional and contralesional NAWM (student’s t-test for dependent samples, Wilcoxon matched pairs test). Histogram DKI data were compared between glioma types and glioma grades (multiple comparisons of mean ranks for all groups). The discriminating potential for DKI in assessing glioma type and grade was assessed with receiver operating characteristics (ROC) curves. Results There were significant differences in all mean DKI variables between perilesional and contralesional NAWM (p=<0.000), except for axial kurtosis (p=0.099). Forty-four histogram variables differed significantly between glioma grades II (n=23) and III (n=12) (p=0.003−0.048) and 10 variables differed significantly between ACs (n=18) and ODs (n=17) (p=0.011−0.050). ROC curves of the best discriminating variables had an area under the curve (AUC) of 0.657−0.815. Conclusions Mean DKI variables in perilesional NAWM differ significantly from contralesional NAWM, suggesting altered microstructure by tumor infiltration not depicted on morphological MRI. Histogram analysis of DKI data identifies differences between glioma grades and subtypes.

Arterial spin labeling MR imaging for differentiation between high- and low-grade glioma—a meta-analysis

Background Arterial spin labeling is an MR imaging technique that measures cerebral blood flow (CBF) non-invasively. The aim of the study is to assess the diagnostic performance of arterial spin labeling (ASL) MR imaging for differentiation between high-grade glioma and low-grade glioma. Methods Cochrane Library, Embase, Medline, and Web of Science Core Collection were searched. Study selection ended November 2017. This study was prospectively registered in PROSPERO (CRD42017080885). Two authors screened all titles and abstracts for possible inclusion. Data were extracted independently by 2 authors. Bivariate random effects meta-analysis was used to describe summary receiver operating characteristics. Trial sequential analysis (TSA) was performed. Results In total, 15 studies with 505 patients were included. The diagnostic performance of ASL CBF for glioma grading was 0.90 with summary sensitivity 0.89 (0.79-0.90) and specificity 0.80 (0.72-0.89). The diagnostic performance was similar between pulsed ASL (AUC 0.90) with a sensitivity 0.85 (0.71-0.91) and specificity 0.83 (0.69-0.92) and pseudocontinuous ASL (AUC 0.88) with a sensitivity 0.86 (0.79-0.91) and specificity 0.80 (0.65-0.87). In astrocytomas, the diagnostic performance was 0.89 with sensitivity 0.86 (0.79 to 0.91) and specificity 0.79 (0.63 to 0.89). Sensitivity analysis confirmed the robustness of the findings. TSA revealed that the meta-analysis was adequately powered. Conclusion Arterial spin labeling MR imaging had an excellent diagnostic accuracy for differentiation between high-grade and low-grade glioma. Given its low cost, non-invasiveness, and efficacy, ASL MR imaging should be considered for implementation in the routine workup of patients with glioma.

Diagnostic accuracy of 11 C-methionine PET in detecting neuropathologically confirmed recurrent brain tumor after radiation therapy

ObjectiveThis study aims to determine the diagnostic test accuracy (DTA) of 11C-methionine (MET) PET in the discrimination between recurrent tumor and radiation-induced injury in neuropathologically confirmed cases.MethodsA retrospective cohort of 30 patients with previously irradiated intracranial tumors (23 gliomas, 6 metastases, and 1 meningioma) was included. All patients underwent a preoperative MET PET and postoperative neuropathological analysis. Maximum and mean standardized uptake values (SUV) were obtained in the lesion, in the contralateral mirror region, and in the contralateral frontal cortex. Lesion-to-background SUV ratios (SUR mirror and SUR cortex) were then calculated. The Mann–Whitney U test was used to evaluate differences in SUV ratios between confirmed recurrent tumor and radiation injury. DTA was determined through receiver operating characteristic (ROC) analysis.ResultsTwenty-one patients had recurrent tumor and nine had radiation injury. The area under the ROC curve (AUC) was 0.89 for SURmaxmirror and 0.88 for SURmaxcortex. The mean (SD) of SURmaxmirror was 2.37 (0.58) in tumor recurrence and 1.57 (0.40) in radiation necrosis (P ≤ 0.001). The corresponding values for SURmaxcortex were 2.13 (0.50) and 1.45 (0.37) (P = 0.001). Clinically relevant cutoffs were SURmaxmirror ≥ 1.99 giving a specificity of 100% for tumor recurrence with a sensitivity of 76% and SURmaxcortex ≥ 1.58 giving a sensitivity and specificity of 90 and 78%, respectively.ConclusionsBased on neuropathologically confirmed cases, the DTA of SURmaxmirror and SURmaxcortex from 11C-methionine PET was high when discriminating recurrent tumor from radiation injury.

Arterial Spin-Labeling in Children with Brain Tumor: A Meta-Analysis

BACKGROUND: The value of arterial spin-labeling in a pediatric population has not been assessed in a meta-analysis. PURPOSE: Our aim was to assess the diagnostic accuracy of arterial spin-labeling–derived cerebral blood flow to discriminate low- and high-grade tumors. DATA SOURCES: MEDLINE, EMBASE, the Web of Science Core Collection, and the Cochrane Library were used. STUDY SELECTION: Pediatric patients with arterial spin-labeling MR imaging with verified neuropathologic diagnoses were included. DATA ANALYSIS: Relative CBF and absolute CBF and tumor grade were extracted, including sequence-specific information. Mean differences in CBF between low- and high-grade tumors were calculated. Study quality was assessed. DATA SYNTHESIS: Data were aggregated using the bivariate summary receiver operating characteristic curve model. Heterogeneity was explored with meta-regression and subgroup analyses. The study protocol was published at PROSPERO (CRD42017075055). Eight studies encompassing 286 pediatric patients were included. The mean differences in absolute CBF were 29.62 mL/min/100 g (95% CI, 10.43–48.82 mL/min/100 g), I2 = 74, P = .002, and 1.34 mL/min/100 g (95% CI, 0.95–1.74 mL/min/100 g), P < .001, I2 = 38 for relative CBF. Pooled sensitivity for relative CBF ranged from 0.75 to 0.90, and specificity, from 0.77 to 0.92 with an area under curve = 0.92. Meta-regression showed no moderating effect of sequence parameters TE, TR, acquisition time, or ROI method. LIMITATIONS: Included tumor types, analysis method, and original data varied among included studies. CONCLUSIONS: Arterial spin-labeling–derived CBF measures showed high diagnostic accuracy for discriminating low- and high-grade tumors in pediatric patients with brain tumors. The relative CBF showed less variation among studies than the absolute CBF.

Self-declared stock ownership and association with positive trial outcome in randomized controlled trials with binary outcomes published in general medical journals: a cross-sectional study

BackgroundDescribe the prevalence and types of conflicts of interest (COI) in published randomized controlled trials (RCTs) in general medical journals with a binary primary outcome and assess the association between conflicts of interest and favorable outcome.MethodsParallel-group RCTs with a binary primary outcome published in three general medical journals during 2013–2015 were identified. COI type, funding source, and outcome were extracted. Binomial logistic regression model was performed to assess association between COI and funding source with outcome.ResultsA total of 509 consecutive parallel-group RCTs were included in the study. COI was reported in 74% in mixed funded RCTs and in 99% in for-profit funded RCTs. Stock ownership was reported in none of the non-profit RCTs, in 7% of mixed funded RCTs, and in 50% of for-profit funded RCTs. Mixed-funded RCTs had employees from the funding company in 11% and for-profit RCTs in 76%. Multivariable logistic regression revealed that stock ownership in the funding company among any of the authors was associated with a favorable outcome (odds ratio = 3.53; 95% confidence interval = 1.59–7.86; p < 0.01).ConclusionCOI in for-profit funded RCTs is extensive, because the factors related to COI are not fully independent, a multivariable analysis should be cautiously interpreted. However, after multivariable adjustment only stock ownership from the funding company among authors is associated with a favorable outcome.

Outcome switching in randomized controlled oncology trials reporting on surrogate endpoints: a cross-sectional analysis

Inconsistent reporting of clinical trials is well-known in the literature. Despite this, factors associated with poor practice such as outcome switching in clinical trials are poorly understood. We performed a cross-sectional analysis to evaluate the prevalence of, and the factors associated with outcome switching. PubMed and Embase were searched for pharmaceutical randomized controlled trials (RCTs) in oncology reporting on a surrogate primary outcome published in 2015. Outcome switching was present in 18% (39/216). First-author male sex was significantly more likely associated with outcome switching compared to female sex with an OR of 3.05 (95% CI 1.07–8.64, p = 0.04) after multivariable adjustment. For-profit funded RCTs were less likely associated with outcome switching compared to non-profit funded research with an OR of 0.22 (95% CI 0.07–0.74, p = 0.01). First author male sex was more likely associated with outcome switching compared to female sex in drug oncology RCTs reporting on a primary surrogate endpoint. For-profit funded research was less likely associated with outcome switching compared to research funded by non-profit organizations. Furthermore, 18 percent of drug oncology trials reporting on a surrogate endpoint could have a higher risk of false positive results due to primary outcome switching.