Between-centre differences and treatment effects in randomized controlled trials: A case study in traumatic brain injury

BACKGROUND: In Traumatic Brain Injury (TBI), large between-centre differences in outcome exist and many clinicians believe that such differences influence estimation of the treatment effect in randomized controlled trial (RCTs). The aim of this study was to assess the influence of between-centre differences in outcome on the estimated treatment effect in a large RCT in TBI. METHODS: We used data from the MRC CRASH trial on the efficacy of corticosteroid infusion in patients with TBI. We analyzed the effect of the treatment on 14 day mortality with fixed effect logistic regression. Next we used random effects logistic regression with a random intercept to estimate the treatment effect taking into account between-centre differences in outcome. Between-centre differences in outcome were expressed with a 95% range of odds ratios (OR) for centres compared to the average, based on the variance of the random effects (tau2). A random effects logistic regression model with random slopes was used to allow the treatment effect to vary by centre. The variation in treatment effect between the centres was expressed in a 95% range of the estimated treatment ORs. RESULTS: In 9978 patients from 237 centres, 14-day mortality was 19.5%. Mortality was higher in the treatment group (OR = 1.22, p = 0.00010). Using a random effects model showed large between-centre differences in outcome (95% range of centre effects: 0.27- 3.71), but did not substantially change the estimated treatment effect (OR = 1.24, p = 0.00003). There was limited, although statistically significant, between-centre variation in the treatment effect (OR = 1.22, 95% treatment OR range: 1.17-1.26). CONCLUSION: Large between-centre differences in outcome do not necessarily affect the estimated treatment effect in RCTs, in contrast to current beliefs in the clinical area of TBI

The association between green space and cause-specific mortality in urban New Zealand: an ecological analysis of green space utility

<b>Background:</b> There is mounting international evidence that exposure to green environments is associated with health benefits, including lower mortality rates. Consequently, it has been suggested that the uneven distribution of such environments may contribute to health inequalities. Possible causative mechanisms behind the green space and health relationship include the provision of physical activity opportunities, facilitation of social contact and the restorative effects of nature. In the New Zealand context we investigated whether there was a socioeconomic gradient in green space exposure and whether green space exposure was associated with cause-specific mortality (cardiovascular disease and lung cancer). We subsequently asked what is the mechanism(s) by which green space availability may influence mortality outcomes, by contrasting health associations for different types of green space. <b>Methods:</b> This was an observational study on a population of 1,546,405 living in 1009 small urban areas in New Zealand. A neighbourhood-level classification was developed to distinguish between usable (i.e., visitable) and non-usable green space (i.e., visible but not visitable) in the urban areas. Negative binomial regression models were fitted to examine the association between quartiles of area-level green space availability and risk of mortality from cardiovascular disease (n = 9,484; 1996 - 2005) and from lung cancer (n = 2,603; 1996 - 2005), after control for age, sex, socio-economic deprivation, smoking, air pollution and population density. <b>Results:</b> Deprived neighbourhoods were relatively disadvantaged in total green space availability (11% less total green space for a one standard deviation increase in NZDep2001 deprivation score, p < 0.001), but had marginally more usable green space (2% more for a one standard deviation increase in deprivation score, p = 0.002). No significant associations between usable or total green space and mortality were observed after adjustment for confounders. <b>Conclusion</b> Contrary to expectations we found no evidence that green space influenced cardiovascular disease mortality in New Zealand, suggesting that green space and health relationships may vary according to national, societal or environmental context. Hence we were unable to infer the mechanism in the relationship. Our inability to adjust for individual-level factors with a significant influence on cardiovascular disease and lung cancer mortality risk (e.g., diet and alcohol consumption) will have limited the ability of the analyses to detect green space effects, if present. Additionally, green space variation may have lesser relevance for health in New Zealand because green space is generally more abundant and there is less social and spatial variation in its availability than found in other contexts

Massive expansion and cryopreservation of functional human induced pluripotent stem cell-derived cardiomyocyte

Since the discovery of human induced pluripotent stem cells (hiPSCs), numerous strategies have been established to efficiently derive cardiomyocytes from hiPSCs (hiPSC-CMs). Here, we describe a cost-effective strategy for the subsequent massive expansion (>250-fold) of high-purity hiPSC-CMs relying on two aspects: removal of cell-cell contacts and small-molecule inhibition with CHIR99021. The protocol maintains CM functionality, allows cryopreservation, and the cells can be used in downstream assays such as disease modeling, drug and toxicity screening, and cell therapy. For complete details on the use and execution of this protocol, please refer to Buikema (2020)

Logopenic and nonfluent variants of primary progressive aphasia are differentiated by acoustic measures of speech production

Differentiation of logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia is important yet remains challenging since it hinges on expert based evaluation of speech and language production. In this study acoustic measures of speech in conjunction with voxel-based morphometry were used to determine the success of the measures as an adjunct to diagnosis and to explore the neural basis of apraxia of speech in nfvPPA. Forty-one patients (21 lvPPA, 20 nfvPPA) were recruited from a consecutive sample with suspected frontotemporal dementia. Patients were diagnosed using the current gold-standard of expert perceptual judgment, based on presence/absence of particular speech features during speaking tasks. Seventeen healthy age-matched adults served as controls. MRI scans were available for 11 control and 37 PPA cases; 23 of the PPA cases underwent amyloid ligand PET imaging. Measures, corresponding to perceptual features of apraxia of speech, were periods of silence during reading and relative vowel duration and intensity in polysyllable word repetition. Discriminant function analyses revealed that a measure of relative vowel duration differentiated nfvPPA cases from both control and lvPPA cases (r2 = 0.47) with 88% agreement with expert judgment of presence of apraxia of speech in nfvPPA cases. VBM analysis showed that relative vowel duration covaried with grey matter intensity in areas critical for speech motor planning and programming: precentral gyrus, supplementary motor area and inferior frontal gyrus bilaterally, only affected in the nfvPPA group. This bilateral involvement of frontal speech networks in nfvPPA potentially affects access to compensatory mechanisms involving right hemisphere homologues. Measures of silences during reading also discriminated the PPA and control groups, but did not increase predictive accuracy. Findings suggest that a measure of relative vowel duration from of a polysyllable word repetition task may be sufficient for detecting most cases of apraxia of speech and distinguishing between nfvPPA and lvPPA

Estimating the prevalence of breast cancer using a disease model: data problems and trends

BACKGROUND: Health policy and planning depend on quantitative data of disease epidemiology. However, empirical data are often incomplete or are of questionable validity. Disease models describing the relationship between incidence, prevalence and mortality are used to detect data problems or supplement missing data. Because time trends in the data affect their outcome, we compared the extent to which trends and known data problems affected model outcome for breast cancer. METHODS: We calculated breast cancer prevalence from Dutch incidence and mortality data (the Netherlands Cancer Registry and Statistics Netherlands) and compared this to regionally available prevalence data (Eindhoven Cancer Registry, IKZ). Subsequently, we recalculated the model adjusting for 1) limitations of the prevalence data, 2) a trend in incidence, 3) secondary primaries, and 4) excess mortality due to non-breast cancer deaths. RESULTS: There was a large discrepancy between calculated and IKZ prevalence, which could be explained for 60% by the limitations of the prevalence data plus the trend in incidence. Secondary primaries and excess mortality had relatively small effects only (explaining 17% and 6%, respectively), leaving a smaller part of the difference unexplained. CONCLUSION: IPM models can be useful both for checking data inconsistencies and for supplementing incomplete data, but their results should be interpreted with caution. Unknown data problems and trends may affect the outcome and in the absence of additional data, expert opinion is the only available judge

A mitochondrial mutator plasmid that causes senescence under dietary restricted conditions

BACKGROUND: Calorie or dietary restriction extends life span in a wide range of organisms including the filamentous fungus Podospora anserina. Under dietary restricted conditions, P. anserina isolates are several-fold longer lived. This is however not the case in isolates that carry one of the pAL2-1 homologous mitochondrial plasmids. RESULTS: We show that the pAL2-1 homologues act as 'insertional mutators' of the mitochondrial genome, which may explain their negative effect on life span extension. Sequencing revealed at least fourteen unique plasmid integration sites, of which twelve were located within the mitochondrial genome and two within copies of the plasmid itself. The plasmids were able to integrate in their entirety, via a non-homologous mode of recombination. Some of the integrated plasmid copies were truncated, which probably resulted from secondary, post-integrative, recombination processes. Integration sites were predominantly located within and surrounding the region containing the mitochondrial rDNA loci. CONCLUSION: We propose a model for the mechanism of integration, based on innate modes of mtDNA recombination, and discuss its possible link with the plasmid's negative effect on dietary restriction mediated life span extension

Multilevel analysis in CSCL Research

Janssen, J., Erkens, G., Kirschner, P. A., & Kanselaar, G. (2011). Multilevel analysis in CSCL research. In S. Puntambekar, G. Erkens, & C. Hmelo-Silver (Eds.), Analyzing interactions in CSCL: Methods, approaches and issues (pp. 187-205). New York: Springer. doi:10.1007/978-1-4419-7710-6_9CSCL researchers are often interested in the processes that unfold between learners in online learning environments and the outcomes that stem from these interactions. However, studying collaborative learning processes is not an easy task. Researchers have to make quite a few methodological decisions such as how to study the collaborative process itself (e.g., develop a coding scheme or a questionnaire), on the appropriate unit of analysis (e.g., the individual or the group), and which statistical technique to use (e.g., descriptive statistics, analysis of variance, correlation analysis). Recently, several researchers have turned to multilevel analysis (MLA) to answer their research questions (e.g., Cress, 2008; De Wever, Van Keer, Schellens, & Valcke, 2007; Dewiyanti, Brand-Gruwel, Jochems, & Broers, 2007; Schellens, Van Keer, & Valcke, 2005; Strijbos, Martens, Jochems, & Broers, 2004; Stylianou-Georgiou, Papanastasiou, & Puntambekar, chapter #). However, CSCL studies that apply MLA analysis still remain relatively scarce. Instead, many CSCL researchers continue to use ‘traditional’ statistical techniques (e.g., analysis of variance, regression analysis), although these techniques may not be appropriate for what is being studied. An important aim of this chapter is therefore to explain why MLA is often necessary to correctly answer the questions CSCL researchers address. Furthermore, we wish to highlight the consequences of failing to use MLA when this is called for, using data from our own studies