Between-centre Variation Research Articles

The role of kidney registries in expediting large-scale collection of patient-reported outcome measures for people with chronic kidney disease

ABSTRACTIn this issue of Clinical Kidney Journal, Van der Willik et al. report findings from a pilot study where they introduced collection of patient-reported outcome measures (PROMs) into routine kidney care in Dutch dialysis centres. It is comparable to a registry-led PROMs initiative in Sweden, published in Clinical Kidney Journal in 2020. Both studies reported low average PROMs response rates with substantial between-centre variation, and both identified suboptimal patient and staff engagement as a key barrier to implementing PROMs in routine care for people with chronic kidney disease (CKD). This suggests that national kidney registries could be well placed to facilitate large-scale collection of PROMs data, but that they may require additional guidance on how to do this successfully. In this editorial, we discuss the current state-of-play of PROMs collection by kidney registries and provide an overview of what is (un)known about the feasibility and effectiveness of PROMs in CKD and other conditions. We anticipate that the fast-growing evidence base on whether, and how, PROMs can be of value in CKD settings will expedite registry-based PROMs collection, which will ultimately lead to more valuable and person-centred services and to enhanced health and well-being of people with CKD.

Use and impact of high intensity treatments in patients with traumatic brain injury across Europe: a CENTER-TBI analysis

PurposeTo study variation in, and clinical impact of high Therapy Intensity Level (TIL) treatments for elevated intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across European Intensive Care Units (ICUs).MethodsWe studied high TIL treatments (metabolic suppression, hypothermia (< 35 °C), intensive hyperventilation (PaCO2 < 4 kPa), and secondary decompressive craniectomy) in patients receiving ICP monitoring in the ICU stratum of the CENTER-TBI study. A random effect logistic regression model was used to determine between-centre variation in their use. A propensity score-matched model was used to study the impact on outcome (6-months Glasgow Outcome Score-extended (GOSE)), whilst adjusting for case-mix severity, signs of brain herniation on imaging, and ICP.Results313 of 758 patients from 52 European centres (41%) received at least one high TIL treatment with significant variation between centres (median odds ratio = 2.26). Patients often transiently received high TIL therapies without escalation from lower tier treatments. 38% of patients with high TIL treatment had favourable outcomes (GOSE ≥ 5). The use of high TIL treatment was not significantly associated with worse outcome (285 matched pairs, OR 1.4, 95% CI [1.0–2.0]). However, a sensitivity analysis excluding high TIL treatments at day 1 or use of metabolic suppression at any day did reveal a statistically significant association with worse outcome.ConclusionSubstantial between-centre variation in use of high TIL treatments for TBI was found and treatment escalation to higher TIL treatments were often not preceded by more conventional lower TIL treatments. The significant association between high TIL treatments after day 1 and worse outcomes may reflect aggressive use or unmeasured confounders or inappropriate escalation strategies.Take home messageSubstantial variation was found in the use of highly intensive ICP-lowering treatments across European ICUs and a stepwise escalation strategy from lower to higher intensity level therapy is often lacking. Further research is necessary to study the impact of high therapy intensity treatments.Trial registrationThe core study was registered with ClinicalTrials.gov, number NCT02210221, registered 08/06/2014, https://clinicaltrials.gov/ct2/show/NCT02210221?id=NCT02210221&draw=1&rank=1 and with Resource Identification Portal (RRID: SCR_015582).

Variability of fitting parameters across cochlear implant centres.

As a follow-up to the studies by Vaerenberg et al. (Sci World J 501738:1-12, 2014) and Browning et al. (Cochlear Implant Int 21(3):1-13, 2020), who used questionnaires, we determined whether there are between-centre variations in the fitting of cochlear implants by analysing the methodology, fitting parameters and hearing results of patients from four centres with real data. The purpose of this study is to highlight the lack of streamlined mapping guides and outcome measures with respect to cochlear implant (CI) fittings. A retrospective study with ninety-seven post-lingual adults with a nucleus cochlear implant placed between 2003 and 2013 was included to ensure at least 5years of follow-up. The studied data were as follows: the methodology, including the fitter's professional background, the method of activation, the sequence of fitting sessions, the objectives measures and hearing outcomes; and the fitting parameters, including the speech processors, programming strategy, stimulation mode, T and C levels, T-SPL and C-SPL, maxima, pulse width, loudness growth and hearing results. This investigation highlights some common practices across professionals and CI centres: the activation of a CI is behavioural; impedances are systematically measured at each fitting; and some parameters are rarely modified. However, there are also differences, either between centres, such as the sequences of fitting sessions (p < 0.05) or their approach to spectral bands (p < 0.05), or even within centres, such as the policy regarding T and C levels at high frequencies compared to those at low and mid-frequencies. There are important variations between and within centres that reflect a lack of CI-related policies and outcome measures in the fitting of CI. NCT03700268.

A computerized decision support system did not improve personalization of exercise-based cardiac rehabilitation according to latest recommendations.

Recent studies showed that exercise-based cardiac rehabilitation (ECR) programmes are often not personalized to individual patient characteristics according to latest recommendations. This study investigates whether a computerized decision support (CDS) system based on latest recommendations and guidelines can improve personalization of ECR prescriptions. Pseudo-randomized intervention study. Among participating Dutch cardiac rehabilitation centres, ECR programme characteristics of consecutive patients were recorded during 1 year. CDS was used during a randomly assigned 4-month period within this year. Primary outcome was concordance to latest recommendations in three phases (before, during, and after CDS) for 12 ECR programme characteristics. Secondary outcome was variation in training characteristics. We recruited ten Dutch CR centres and enrolled 2258 patients to the study. Overall concordance of ECR prescriptions was 59.9% in Phase 1, 62.1% in Phase 2 (P = 0.82), and 59.9% in Phase 3 (P = 0.56). Concordance varied from 0.0% to 99.9% for the 12 ECR characteristics. There was significant between-centre variation for most training characteristics in Phases 1 and 2. In Phase 3, there was only a significant variation for aerobic and resistance training intensity (P = 0.01), aerobic training volume (P < 0.01), and the number of strengthening exercises but no longer for the other characteristics. Aerobic training volume was often below recommended (28.2%) and declined during the study. CDS did not substantially improve concordance with ECR prescriptions. As aerobic training volume was often lower than recommended and reduced during the study, a lack of institutional resources might be an important barrier in personalizing ECR prescriptions.

Enteral Feeding of Children on Noninvasive Respiratory Support: A Four-Center European Study.

To explore enteral feeding practices and the achievement of energy targets in children on noninvasive respiratory support, in four European PICUs. A four-center retrospective cohort study. Four PICUs: Bristol, United Kingdom; Lyon, France; Madrid, Spain; and Rotterdam, The Netherlands. Children in PICU who required acute noninvasive respiratory support in the first 7 days. The primary outcome was achievement of standardized kcal/goal. None. A total of 325 children were included (Bristol 104; Lyon 99; Madrid 72; and Rotterdam 50). The median (interquartile range) age and weight were 3 months (1-16 mo) and 5 kg (4-10 mo), respectively, with 66% admitted with respiratory failure. There were large between-center variations in practices. Overall, 190/325 (58.5%) received noninvasive respiratory support in order to prevent intubation and 41.5% after extubation. The main modes of noninvasive respiratory support used were high-flow nasal cannula 43.6%, bilevel positive airway pressure 33.2%, and continuous positive airway pressure 21.2%. Most children (77.8%) were fed gastrically (48.4% continuously) and the median time to the first feed after noninvasive respiratory support initiation was 4 hours (interquartile range, 1-9 hr). The median percentage of time a child was nil per oral while on noninvasive respiratory support was 4 hours (2-13 hr). Overall, children received a median of 56% (25-82%) of their energy goals compared with a standardized target of 0.85 of the recommended dietary allowance. Patients receiving step-up noninvasive respiratory support (p = < 0.001), those on bilevel positive airway pressure or continuous positive airway pressure (compared with high-flow nasal cannula) (p = < 0.001), and those on continuous feeds (p = < 0.001) achieved significantly more of their kcal goal. Gastrointestinal complications varied from 4.8-20%, with the most common reported being vomiting in 54/325 (16.6%), other complications occurred in 40/325 (12.3%) children, but pulmonary aspiration was rare 5/325 (1.5%). Children on noninvasive respiratory support tolerated feeding well, with relatively few complications, but prospective trials are now required to determine the optimal timing and feeding method for these children.

Quality indicators for patients with traumatic brain injury in European intensive care units: a CENTER-TBI study

BackgroundThe aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measurement and improvement.MethodsOur analysis was based on 2006 adult patients admitted to 54 ICUs between 2014 and 2018, enrolled in the CENTER-TBI study. Indicator scores were calculated as percentage adherence for structure and process indicators and as event rates or median scores for outcome indicators. Feasibility was quantified by the completeness of the variables. Discriminability was determined by the between-centre variation, estimated with a random effect regression model adjusted for case-mix severity and quantified by the median odds ratio (MOR). Statistical uncertainty of outcome indicators was determined by the median number of events per centre, using a cut-off of 10.ResultsA total of 26/42 indicators could be calculated from the CENTER-TBI database. Most quality indicators proved feasible to obtain with more than 70% completeness. Sub-optimal adherence was found for most quality indicators, ranging from 26 to 93% and 20 to 99% for structure and process indicators. Significant (p < 0.001) between-centre variation was found in seven process and five outcome indicators with MORs ranging from 1.51 to 4.14. Statistical uncertainty of outcome indicators was generally high; five out of seven had less than 10 events per centre.ConclusionsOverall, nine structures, five processes, but none of the outcome indicators showed potential for quality improvement purposes for TBI patients in the ICU. Future research should focus on implementation efforts and continuous reevaluation of quality indicators.Trial registrationThe core study was registered with ClinicalTrials.gov, number NCT02210221, registered on August 06, 2014, with Resource Identification Portal (RRID: SCR_015582).

Service Level Factors Associated with Cervical Screening in Aboriginal and Torres Strait Islander Primary Health Care Centres in Australia.

Aboriginal and Torres Strait Islander women have significantly higher cervical cancer incidence and mortality than other Australian women. In this study, we assessed the documented delivery of cervical screening for women attending Indigenous Primary Health Care (PHC) centres across Australia and identified service-level factors associated with between-centre variation in screening coverage. We analysed 3801 clinical audit records for PHC clients aged 20–64 years from 135 Indigenous PHC centres participating in the Audit for Best Practice in Chronic Disease (ABCD) continuous quality improvement (CQI) program across five Australian states/territories during 2005 to 2014. Multilevel logistic regression models were used to identify service-level factors associated with screening, while accounting for differences in client-level factors. There was substantial variation in the proportion of clients who had a documented cervical screen in the previous two years across the participating PHC centres (median 50%, interquartile range (IQR): 29–67%), persisting over years and audit cycle. Centre-level factors explained 40% of the variation; client-level factors did not reduce the between-centre variation. Screening coverage was associated with longer time enrolled in the CQI program and very remote location. Indigenous PHC centres play an important role in providing cervical screening to Aboriginal and Torres Strait Islander women. Thus, their leadership is essential to ensure that Australia’s public health commitment to the elimination of cervical cancer includes Aboriginal and Torres Strait Islander women. A sustained commitment to CQI may improve PHC centres delivery of cervical screening; however, factors that may impact on service delivery, such as organisational, geographical and environmental factors, warrant further investigation.

Geographical variations in the prevalence of hypertension in France: Cross-sectional analysis of the CONSTANCES cohort.

While international variations in the prevalence of hypertension are well described, less is known about intra-national disparities and their determinants. We wanted to describe the variations in hypertension prevalence within France and to determine how much lifestyle and socioeconomic factors contributed to explain these regional variations. Participants (62,247 French adults aged 18 to 69 years) were recruited in the 16 centres of the CONSTANCES study between 2012 and 2015. Hypertension was defined as blood pressure higher than 140/90 mmHg and/or taking antihypertensive medications. The contribution of lifestyle and socioeconomic factors to hypertension prevalence variations among centres was examined using sequential hierarchical logistic models. Hypertension prevalence was 37.3% (95% confidence interval (CI) = 36.6-38.0) in men and 23.2% (95% CI = 22.7-23.8) in women. Hypertension prevalence rates varied by almost two-fold among centres (1.9 in men, 1.6 in women) with the highest prevalence in the north and the east of France. Body mass index was strongly associated with hypertension in women (odds ratio (OR)1-unit increase = 1.11 (95% CI = 1.11-1.12)) and was the highest contributor to between-centre variations (27% in women), followed by socioeconomic characteristics (e.g. ORhigh versus low education = 0.85 (95% CI = 0.83-0.87), contributing to 14% of variations in women). Together, family history of hypertension, body mass index, education, occupation and residential area socioeconomic level explained about 30% and 40% of between-centre variations in men and women, respectively. Hypertension prevalence greatly varies among French regions and this is partly explained by known lifestyle and socioeconomic factors. Nevertheless, these variations and all the hypertension determinants have not been fully deciphered yet.

Variation in hepatitis C virus treatment uptake between Canadian centres in the era of direct-acting antivirals

BackgroundPatients co-infected with HIV and hepatitis C virus (HCV) are a priority target for HCV treatment. The simplicity and efficacy of direct-acting antivirals (DAA) should help overcome patient, provider, and structural barriers to scaling up treatment. MethodsWe estimated between-centre variation in DAA treatment uptake among 1734 patients enrolled at the 18 centres of the Canadian Co-Infection Cohort—a prospective cohort of adults co-infected with HIV and HCV. We then compared this variation to that observed during the interferon era. Time to treatment uptake was modeled using a Weibull time-to-event model adjusting for centre and patient characteristics thought to have an impact on treatment initiation in the DAA era. ResultsAt the time of administrative censoring (December 31, 2016), 981 cohort participants were eligible for second-generation DAA therapy (HCV RNA positive after November 21, 2013) of whom 278 initiated DAAs (16 patients per 100 person-years). Patients with low monthly income, Indigenous ethnicity, recent injection drug use, HCV genotype 3, or unknown HCV genotype were less likely to start treatment. After adjusting for patient characteristics, the estimated between-centre variance (σ2) was 0.29 (95% credible interval [CrI]: 0.09-0.89), considerably lower than during the interferon era (σ2 = 0.87, 95% CrI: 0.49–1.5). This between-centre variance was further reduced by the addition of centre-level effects for jurisdiction (σ2 = 0.15, 95% CrI: 0.02-0.60). ConclusionMuch of the variation in treatment uptake between centres can now be attributed to regional differences. This suggests that after the introduction of DAAs, treatment barriers have shifted towards prescribing and reimbursement restrictions based on liver fibrosis, which vary by jurisdiction. The removal of these restrictions, however, will need to be paired with strategies to overcome patient-level barriers, which continue to prevent marginalized people and active substance users from accessing treatment.

Can environment or allergy explain international variation in prevalence of wheeze in childhood?

Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8-12year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre-level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, mother's smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence.

Factors affecting local regrowth after watch and wait for patients with a clinical complete response following chemoradiotherapy in rectal cancer (InterCoRe consortium): an individual participant data meta-analysis

In patients with rectal cancer who achieve clinical complete response after neoadjuvant chemoradiotherapy, watch and wait is a novel management strategy with potential to avoid major surgery. Study-level meta-analyses have reported wide variation in the proportion of patients with local regrowth. We did an individual participant data meta-analysis to investigate factors affecting occurrence of local regrowth. We updated search results of a recent systematic review by searching MEDLINE and Embase from Jan 1, 2016, to May 5, 2017, and used expert knowledge to identify published studies reporting on local regrowth in patients with rectal cancer managed by watch and wait after clinical complete response to neoadjuvant chemoradiotherapy. We restricted studies to those that defined clinical complete response using criteria equivalent to São Paulo benchmarks (ie, absence of residual ulceration, stenosis, or mass within the rectum on clinical and endoscopic examination). The primary outcome was 2-year cumulative incidence of local regrowth, estimated with a two-stage random-effects individual participant data meta-analysis. We assessed the effects of clinical and treatment factors using Cox frailty models, expressed as hazard ratios (HRs). From these models, we derived percentage differences in mean θ as an approximation of the effect of measured covariates on between-centre heterogeneity. This study is registered with PROSPERO, number CRD42017070934. We obtained individual participant data from 11 studies, including 602 patients enrolled between March 11, 1990, and Feb 13, 2017, with a median follow-up of 37·6 months (IQR 25·0-58·7). Ten of the 11 datasets were judged to be at low risk of bias. 2-year cumulative incidence of local regrowth was 21·4% (random-effects 95% CI 15·3-27·6), with high levels of between-study heterogeneity (I2=61%). We noted wide between-centre variation in patient, tumour, and treatment characteristics. We found some evidence that increasing cT stage was associated with increased risk of local regrowth (random-effects HR per cT stage 1·40, 95% CI 1·00-1·94; ptrend=0·048). In a subgroup of 459 patients managed after 2008 (when pretreatment staging by MRI became standard), 2-year cumulative incidence of local regrowth was 19% (95% CI 13-28) for stage cT1 and cT2 tumours, 31% (26-37) for cT3, and 37% (21-60) for cT4 (random-effects HR per cT stage 1·50, random-effects 95% CI 1·03-2·17; ptrend=0·0330). We estimated that measured factors contributed 4·8-45·3% of observed between-centre heterogeneity. In patients with rectal cancer and clinical complete response after chemoradiotherapy managed by watch and wait, we found some evidence that increasing cT stage predicts for local regrowth. These data will inform clinician-patient decision making in this setting. Research is needed to determine other predictors of a sustained clinical complete response. None.

Centre-level variation in speech outcome and interventions, and factors associated with poor speech outcomes in 5-year-old children with non-syndromic unilateral cleft lip andpalate: The Cleft Care UK study. Part 4.

To investigate centre-level variation in speech intervention and outcome and factors associated with a speech disorder in children in Cleft Care UK (CCUK). Two hundred and sixty-eight 5-year-old British children with non-syndromic unilateral cleft lip and palate recruited to CCUK. Centre-based therapists undertook audio-video recordings. Perceptual analysis was undertaken using the CAPS-A tool. Speech outcomes were based on structural and articulation scores, and intelligibility/distinctiveness. Between-centre variation in treatment and outcomes were examined using multilevel models. These models were extended to estimate the association between a range of factors (hearing loss, speech intervention, fistula, secondary speech surgery for velopharyngeal insufficiency, socio-economic status, gender, and parental happiness with speech) and speech outcomes. There was centre-level variation in secondary speech surgery, speech intervention, structure and intelligibility outcomes. Children with a history of speech intervention had a lower odds of poor intelligibility/distinctiveness, 0.1 (95% CI: 0.0-0.4). Parental concern was associated with a higher odds of poor intelligibility/distinctiveness, 13.2 (95% CI: 4.9-35.1). Poor speech outcomes were associated with a fistula, secondary speech surgery and history of hearing loss. Within the centralized service there is centre-level variation in secondary speech surgery, intervention and speech outcomes. These findings support the importance of early management of fistulae, effective management of velopharyngeal insufficiency and hearing impairment, and most importantly speech intervention in the preschool years. Parental concern about speech is a good indicator of speech status.

Is there a dose-response relationship of metformin treatment in patients with polycystic ovary syndrome? Results from a multicentric study

Do different dosages of metformin account for different clinical and biochemical outcomes in women with polycystic ovary syndrome (PCOS) and do basal anthropometric and metabolic characteristics of the patients provide any indications regarding the dose required to reach the target effect? Different doses of metformin exerted the same effects on clinical, biochemical and metabolic parameters in patients affected by PCOS. Since the insulin-sensitizing agents came into use in the management of PCOS, metformin has shown a positive benefits-risks ratio. Nonetheless, therapeutic schedules are not well standardized. This is the first study which systematically analyses the effect of different doses of metformin on clinical, hormonal and metabolic features of PCOS. On the basis of our results, higher doses are no more effective than lower doses. A multicentric cohort prospective study. A total of 250 PCOS women were enrolled, 49 lost to follow-up. Menstrual cyclicity, hormonal assays, oral glucose tolerance test, lipid profile and ultrasonographic pelvic examination were evaluated at the baseline and after 6 months of metformin treatment at different doses (1000, 1500 and 1700 mg). A total of 201 PCOS patients completed the study without protocol violations in three university hospitals: seventy-three patients from Centre A (treated with metformin 500 mg twice a day), 60 patients from Centre B (treated with metformin 500 mg three times a day) and 68 patients from Centre C (treated with metformin 850 mg twice a day). Metformin exerted an overall positive effect on the clinical and endocrine-metabolic features of PCOS. The degree of these effects was independent of the administered dosage in every range of basal body mass index (BMI). When patients were stratified according to their insulinaemic status, scattered inter-doses differences were found in some of the outcome measures. Patients who exhibited an increase of >2 menstrual cycles/year were considered as responders to treatment. Responders had a higher basal BMI than non-responders and showed a greater reduction in plasma testosterone levels after metformin treatment, but other outcome measures did not differ significantly. Total insulin secretion in the 180 min following the glucose tolerance test before metformin treatment (basal AUC-I) was significantly correlated with the decrease in insulin secretion induced by metformin in both the whole group and in responders, but only correlated with the variation in the number of cycles in responders. The different doses were administered in different centres, and between-centre variation is a potential confounding factor. The paradigm of using the minimum effective dose of metformin could be pursued in other pathological conditions characterized by insulin resistance. No funding or competing interests to declare.

Coagulometer international sensitivity index (ISI) derivation, a rapid method using the prothrombin time/international normalized ratio (PT/INR) Line: a multicenter study

The original WHO procedure for prothrombin time (PT) standardization has been almost entirely abandoned because of the universal use of PT coagulometers. These often give different international normalized ratio (INR) results from the manual method, between individual makes of instruments and with instruments from the same manufacture. A simple procedure is required to derive local INR with coagulometers. The PT/INR Line method has recently been developed using five European Concerted Action on Anticoagulation (ECAA) certified plasmas to derive local INR. This procedure has been modified to derive a coagulometer PT/INR Line providing International Sensitivity Index (ISI) and mean normal PT (MNPT) for coagulometers and give local INR. Results have been compared with conventional ISI calibrations at the same laboratories. With human thromboplastins, mean ISI by local calibration was 0.93 (range: 0.77-1.16). With the PT/INR Line, mean coagulometer ISI was higher, for example 0.99 (0.84-1.23) but using the PT/INR Line derived MNPT there was no difference in local INR. Between-centre INR variation of a certified validation plasma was reduced with human and bovine reagents after correction with local ISI calibrations and the PT/INR Line. The PT/INR Line-ISI with its derived MNPT is shown to provide reliable local INR with the 13 different reagent/coagulometer combinations at the 28 centres in this international study.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

Multicentre imaging measurements for oncology and in the brain

Multicentre imaging studies of brain tumours (and other tumour and brain studies) can enable a large group of patients to be studied, yet they present challenging technical problems. Differences between centres can be characterised, understood and minimised by use of phantoms (test objects) and normal control subjects. Normal white matter forms an excellent standard for some MRI parameters (e.g. diffusion or magnetisation transfer) because the normal biological range is low (<2-3%) and the measurements will reflect this, provided the acquisition sequence is controlled. MR phantoms have benefits and they are necessary for some parameters (e.g. tumour volume). Techniques for temperature monitoring and control are given. In a multicentre study or treatment trial, between-centre variation should be minimised. In a cross-sectional study, all groups should be represented at each centre and the effect of centre added as a covariate in the statistical analysis. In a serial study of disease progression or treatment effect, individual patients should receive all of their scans at the same centre; the power is then limited by the within-subject reproducibility. Sources of variation that are generic to any imaging method and analysis parameters include MR sequence mismatch, B(1) errors, CT effective tube potential, region of interest generation and segmentation procedure. Specific tissue parameters are analysed in detail to identify the major sources of variation and the most appropriate phantoms or normal studies. These include dynamic contrast-enhanced and dynamic susceptibility contrast gadolinium imaging, T(1), diffusion, magnetisation transfer, spectroscopy, tumour volume, arterial spin labelling and CT perfusion.

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

BackgroundIn 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.MethodsWe 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.ResultsIn 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).ConclusionLarge 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.

Improving guideline adherence for cardiac rehabilitation in the Netherlands

BackgroundIn 2004, the Netherlands Society of Cardiology released the current guideline on cardiac rehabilitation. Given its complexity and the involvement of various healthcare disciplines, it was supplemented with a clinical algorithm, serving to facilitate its implementation in daily practice. Although the algorithm was shown to be effective for improving guideline adherence, several shortcomings and deficiencies were revealed. Based on these findings, the clinical algorithm has now been updated. This article describes the process and the changes that were made.MethodsThe revision consisted of three phases. First, the reliability of the measurement instruments included in the 2004 Clinical Algorithm was investigated by evaluating between-centre variations of the baseline assessment data. Second, based on the available evidence, a multidisciplinary expert advisory panel selected items needing revision and provided specific recommendations. Third, a guideline development group decided which revisions were finally included, also taking practical considerations into account.ResultsA total of nine items were revised: three because of new scientific insights and six because of the need for more objective measurement instruments. In all revised items, subjective assessment methods were replaced by more objective assessment tools (e.g. symptom-limited exercise instead of clinical judgement). In addition, four new key items were added: screening for anxiety/depression, stress, cardiovascular risk profile and alcohol consumption.ConclusionBased on previously determined shortcomings, the Clinical Algorithm for Cardiac Rehabilitation was thoroughly revised mainly by incorporating more objective assessment methods and by adding several new key areas.

Serum calcium, phosphate, parathyroid hormone, albumin, aluminium and cholesterol achievement on replacement therapy (Chapter 9)

In the UK, there is a continuing year-on-year trend towards improvement in serum phosphate control in dialysis patients although overall it still remains poor. The Renal Association (RA) target (<1.8 mmol/l) was achieved in 65% of patients overall, (71% of peritoneal dialysis (PD) patients, 63% of haemo dialysis (HD) patients). Seventy-six percent of UK dialysis patients achieve a corrected calcium concentration within the RA target range. As with serum phosphate, there is a trend of continuing year-on-year improvement. Nearly two-thirds (69%) of patients achieve a calcium x phosphate product within the KDOQI guidelines (<4.4 mmol(2)/l(2)): again, achievement seems to have improved year-on-year. Control was better in PD patients compared with HD patients (73% vs 67% achieving the standard). There remains large between-centre variation in the ability of renal centres to achieve the UK RA target for plasma parathyroid hormone (PTH). As seen in previous years, overall achievement was poor (median 63%, range 47-92% compliance with the standard). Most transplant patients achieve good phosphate and calcium control (99%, range 95-100%) and the percentage of patients achieving serum calcium concentrations within the target range was 84% (range 43-97%). Nearly all (99%) of transplant patients achieved calcium x phosphate product concentrations within the KDOQI target range. There would appear to be wide variation in clinical practice with respect to aluminium monitoring with a suggestion that few centres are following current UK, RA guidelines. Overall in the UK, 83% of HD, 70% of PD and 62% of transplant patients achieve a total cholesterol concentration <5 mmol/l. The percentage of patients with cholesterol <5 mmol/l has increased significantly year-on-year in all three modalities.

Research governance impediments to clinical trials: a retrospective survey

We sought to evaluate the delays, between-centre variations in practice, and opportunity costs attributable to delays in research governance approval of clinical trials in the United Kingdom.Retrospective survey.Research and Development (R&D) departments at 50 UK National Health Service hospital trusts governing 57 hospital sites.R&D departments participating in four randomized multicentre clinical trials coordinated by our Neurosciences Trials Unit.None.Median delay between application and research governance approval.Only half of the R&D departments used the UK online R&D form. Only a single copy of the application was required by 96% of R&D departments. The median delay between application and research governance approval was 44 working days (inter-quartile range 23-80). A delay of >20 working days was incurred by 43 applications (75%), of which 24 (56%) were not explicable and 11 (20%) were attributable to local funding negotiations. Based on the trial randomization rates at each centre, 108 patients (17% of all patients randomized) could have been randomized during the delay, at a crude cost to funding agencies of 53,743 pounds; if a four week delay was deemed acceptable, 75 patients (12% of all patients randomized) could have been randomized during unacceptable delays, at a crude cost to funding agencies of 37,700 pounds.The UK research governance system incurs unacceptably long and costly delays for clinical trials. Urgent reform is needed, including rapid design and uniform implementation of the 'bureaucracy busting' measures in Best Research for Best Health.