Analysing cluster randomised controlled trials using GLMM, GEE1, GEE2, and QIF: results from four case studies.

BACKGROUND: Using four case studies, we aim to provide practical guidance and recommendations for the analysis of cluster randomised controlled trials. METHODS: Four modelling approaches (Generalized Linear Mixed Models with parameters estimated by maximum likelihood/restricted maximum likelihood; Generalized Linear Models with parameters estimated by Generalized Estimating Equations (1st order or second order) and Quadratic Inference Function, for analysing correlated individual participant level outcomes in cluster randomised controlled trials were identified after we reviewed the literature. We systematically searched the online bibliography databases of MEDLINE, EMBASE, PsycINFO (via OVID), CINAHL (via EBSCO), and SCOPUS. We identified the above-mentioned four statistical analytical approaches and applied them to four case studies of cluster randomised controlled trials with the number of clusters ranging from 10 to 100, and individual participants ranging from 748 to 9,207. Results were obtained for both continuous and binary outcomes using R and SAS statistical packages. RESULTS: The intracluster correlation coefficient (ICC) estimates for the case studies were less than 0.05 and are consistent with the observed ICC values commonly reported in primary care and community-based cluster randomised controlled trials. In most cases, the four methods produced similar results. However, in a few analyses, quadratic inference function produced different results compared to the generalized linear mixed model, first-order generalized estimating equations, and second-order generalized estimating equations, especially in trials with small to moderate numbers of clusters. CONCLUSION: This paper demonstrates the analysis of cluster randomised controlled trials with four modelling approaches. The results obtained were similar in most cases, however, for trials with few clusters we do recommend that the quadratic inference function should be used with caution, and where possible a small sample correction should be used. The generalisability of our results is limited to studies with similar features to our case studies, for example, studies with a similar-sized ICC. It is important to conduct simulation studies to comprehensively evaluate the performance of the four modelling approaches.

Catheter insertion techniques for improving catheter function and clinical outcomes in peritoneal dialysis patients.

BACKGROUND: Peritoneal dialysis (PD) relies on the optimal functionality of the flexible plastic PD catheter present within the peritoneal cavity to enable effective treatment. As a result of limited evidence, it is uncertain if the PD catheter's insertion method influences the rate of catheter dysfunction and, thus, the quality of dialysis therapy. Numerous variations of four basic techniques have been adopted in an attempt to improve and maintain PD catheter function. This review evaluates the association between PD catheter insertion technique and associated differences in  PD catheter function and post-PD catheter insertion complications OBJECTIVES: Our aims were to 1) evaluate if a specific technique used for PD catheter insertion has lower rates of PD catheter dysfunction (early and late) and technique failure; and 2) examine if any of the available techniques results in a reduction in post-procedure complication rates including postoperative haemorrhage, exit-site infection and peritonitis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 24 November 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) examining adults and children undergoing PD catheter insertion. The studies examined any two PD catheter insertion techniques, including laparoscopic, open-surgical, percutaneous and peritoneoscopic insertion. Primary outcomes of interest were PD catheter function and technique survival.  DATA COLLECTION AND ANALYSIS: Two authors independently performed data extraction and assessed the risk of bias for all included studies. Main outcomes in the Summary of Findings tables include primary outcomes - early PD catheter function, long-term PD catheter function, technique failure and postoperative complications. A random effects model was used to perform meta-analyses; risk ratios (RRs) were calculated for dichotomous outcomes, and mean differences (MD) were calculated for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. The certainty of the evidence was evaluated using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach.  MAIN RESULTS: Seventeen studies were included in this review. Nine studies were suitable for inclusion in quantitative meta-analysis (670 randomised participants). Five studies compared laparoscopic with open PD catheter insertion, and four studies compared a 'medical' insertion technique with open surgical PD catheter insertion: percutaneous (2) and peritoneoscopic (2). Random sequence generation was judged to be at low risk of bias in eight studies. Allocation concealment was reported poorly, with only five studies judged to be at low risk of selection bias. Performance bias was judged to be high risk in 10 studies. Attrition bias and reporting bias were judged to be low in 14 and 12 studies, respectively. Six studies compared laparoscopic PD catheter insertion with open surgical insertion. Five studies could be meta-analysed (394 participants). For our primary outcomes, data were either not reported in a format that could be meta-analysed (early PD catheter function, long-term catheter function) or not reported at all (technique failure). One death was reported in the laparoscopic group and none in the open surgical group. In low certainty evidence, laparoscopic PD catheter insertion may make little or no difference to the risk of peritonitis (4 studies, 288 participants: RR 0.97, 95% CI 0.63 to 1.48; I² = 7%), PD catheter removal (4 studies, 257 participants: RR 1.15, 95% CI 0.80 to 1.64; I² = 0%), and dialysate leakage (4 studies, 330 participants: RR 1.40, 95% CI 0.49 to 4.02; I² = 0%), but may reduce the risk of haemorrhage (2 studies, 167 participants: RR 1.68, 95% CI 0.28 to 10.31; I² = 33%) and catheter tip migration (4 studies, 333 participants: RR 0.43, 95% CI 0.20 to 0.92; I² = 12%). Four studies compared a medical insertion technique with open surgical insertion (276 participants). Technique failure was not reported, and no deaths were reported (2 studies, 64 participants). In low certainty evidence, medical insertion may make little or no difference to early PD catheter function (3 studies, 212 participants: RR 0.73, 95% CI 0.29 to 1.83; I² = 0%), while one study reported long-term PD function may improve with peritoneoscopic insertion (116 participants: RR 0.59, 95% CI 0.38 to 0.92). Peritoneoscopic catheter insertion may reduce the episodes of early peritonitis (2 studies, 177 participants: RR 0.21, 95% CI 0.06 to 0.71; I² = 0%) and dialysate leakage (2 studies, 177 participants: RR 0.13, 95% CI 0.02 to 0.71; I² = 0%). Medical insertion had uncertain effects on catheter tip migration (2 studies, 90 participants: RR 0.74, 95% CI 0.15 to 3.73; I² = 0%). Most of the studies examined were small and of poor quality, increasing the risk of imprecision. There was also a significant risk of bias therefore cautious interpretation of results is advised. AUTHORS' CONCLUSIONS: The available studies show that the evidence needed to guide clinicians in developing their PD catheter insertion service is lacking. No PD catheter insertion technique had lower rates of PD catheter dysfunction. High-quality, evidence-based data are urgently required, utilising multi-centre RCTs or large cohort studies, in order to provide definitive guidance relating to PD catheter insertion modality.

Non-urgent emergency department attendances in children: a retrospective observational analysis.

INTRODUCTION: A significant proportion of ED attendances in children may be non-urgent attendances (NUAs), which could be better managed elsewhere. This study aimed to quantify NUAs and urgent attendances (UAs) in children to ED and determine which children present in this way and when. METHODS: Dataset extracted from the CUREd research database containing linked data on the provision of care in Yorkshire and Humber. Analysis focused on children's ED attendances (April 2014-March 2017). Summary statistics and odds ratios (OR) comparing NUAs and UAs were examined by: age, mode and time of arrival and deprivation alongside comparing summary statistics for waiting, treatment and total department times. RESULTS: NUAs were more likely in younger children: OR for NUA in children aged 1-4 years, 0.82 (95% CI: 0.80 to 0.83), age 15 years, 0.39 (95% CI: 0.38 to 0.40), when compared with those under 1 year. NUAs were more likely to arrive out of hours (OOHs) compared with in hours: OR 1.19 (95% CI 1.18 to 1.20), and OOHs arrivals were less common in older children compared with those under 1 year: age 1-4 years, 0.87 (95% CI: 0.84 to 0.89) age 15 years, 0.66 (95% CI: 0.63 to 0.69). NUAs also spent less total time in the ED, with a median (IQR) of 98 min (60-147) compared with 127 min (80-185) for UAs. CONCLUSION: A substantial proportion of ED attendances in children are NUAs. Our data suggest there are particular groups of children for whom targeted interventions would be most beneficial. Children under 5 years would be such a group, particularly in providing accessible, timely care outside of usual community care opening hours.

Paediatric emergency department utilisation rates and maternal migration status in the Born in Bradford cohort: A cross-sectional study.

BACKGROUND: Globally, international migration is increasing. Population growth, along with other demographic changes, may be expected to put new pressures on healthcare systems. Some studies across Europe suggest that emergency departments (EDs) are used more, and differently, by migrants compared to non-migrant populations, which may be a result of unfamiliarity with the healthcare systems and difficulties accessing primary healthcare. However, little evidence exists to understand how migrant parents, who are typically young and of childbearing age, utilise EDs for their children. This study aimed to examine the association between paediatric ED utilisation in the first 5 years of life and maternal migration status in the Born in Bradford (BiB) cohort study. METHODS AND FINDINGS: We analysed linked data from the BiB study-an ongoing, multi-ethnic prospective birth cohort study in Bradford. Bradford is a large, ethnically diverse city in the north of England. In 2017, more than a third of births in Bradford were to mothers who were born outside the UK. Between March 2007 and December 2010, pregnant women were recruited to BiB during routine antenatal care, and the children born to these mothers have been, and continue to be, followed over time to assess how social, genetic, environmental, and behavioural factors impact on health from childhood to adulthood. Data analysed in this study included baseline questionnaire data from BiB mothers, and Bradford Royal Infirmary ED episode data for their children. Main outcomes were likelihood of paediatric ED use (no visits versus at least 1 ED visit in the first 5 years of life) and ED utilisation rates (number and frequency of ED visits) for children who have accessed the ED. The main explanatory variable was mother's migrant status (foreign-born versus UK/Irish-born). Multivariable analyses (logistic and zero-truncated negative binomial regression) were conducted adjusting for socio-demographic and socio-economic factors. The final dataset included 10,168 children born between April 2007 and June 2011, of whom 35.6% were born to migrant mothers. Foreign-born mothers originated from South Asia (28.6%), Europe/Central Asia (3.2%), Africa (2.1%), East Asia/Pacific (1.1%), and the Middle East (0.6%). At recruitment the mothers ranged in age from 15 to 49 years old. Overall, 3,104 (30.5%) children had at least 1 ED visit in the first 5 years of life, with the highest proportion of visits being in the first year of life (36.7%). The proportion of children who visited the ED at least once was lower for children of migrant mothers as compared to children of non-migrant mothers (29.4% versus 31.2%). Children of migrant mothers were found to be less likely to visit the ED (odds ratio 0.88 [95% CI 0.80 to 0.97], p = 0.012). However, among children who visited the ED, the utilisation rate was significantly higher for children of migrant mothers (incidence rate ratio [IRR] 1.19 [95% CI 1.01 to 1.40], p = 0.040). Utilisation rates were higher for children born to mothers from Europe (IRR 1.71 [95% CI 1.07 to 2.71], p = 0.024) and established migrants (≥5 years living in UK) (IRR 1.24 [95% CI 1.02 to 1.51], p = 0.032) compared to UK/Irish-born mothers. Important limitations include being unable to measure children's underlying health status and the urgency of ED attendance, as well as the analysis being limited by missing data. CONCLUSIONS: In this study we observed that there is no higher likelihood of first paediatric ED attendance in the first 5 years of life for children in the BiB cohort for migrant mothers. However, among ED users, children of migrant mothers attend the service more frequently than children of UK/Irish-born mothers. Our findings show that patterns of ED utilisation differ by mother's region of origin and time since arrival in the UK.

The prevalence and natural history of normocalcaemic hypoparathyroidism in a United Kingdom referral population.

CONTEXT: Normocalcaemic hypoparathyroidism (NHYPO) is characterized by low levels of parathyroid hormone (PTH) with normal levels of calcium. There is little in the current literature on this disease, with only two studies published on its prevalence, while its natural history remains relatively unknown. OBJECTIVES: To identify the prevalence of NHYPO in a UK referral population and to study the natural history of the disorder. DESIGN: Retrospective study. Five-year follow-up. PATIENTS: 6280 patients referred for a BMD measurement in a Metabolic Bone referral centre. MEASUREMENTS: Prevalence of NHYPO and variability of calcium. RESULTS: Based on laboratory results on the index day, 22 patients with NHYPO were identified. Four patients were excluded due to non-PTH-induced hypocalcaemia and unconfirmed data. The final prevalence was 0.29%. Only 67% had persistent normocalcaemia, and the rest had intermittent hypocalcaemia. Two of these patients also had persistently low PTH on two occasions. Most of the patients had one PTH measurement available. No patient developed permanent hypoparathyroidism. CONCLUSIONS: The prevalence calculated from this UK referral population is lower when compared to results from previous studies. NHYPO patients often have episodes of hypocalcaemia with some cases having no apparent reason for calcium levels below the reference range.

Urgent care axis for the older adult: where is best to target interventions?

BACKGROUND: We explored the urgent care axis across EDs in Yorkshire and Humber (Y&H) for patients aged ≥75 years to identify where interventions could be targeted to prevent ED attendances and inpatient admissions. METHODS: Hospital Episode Statistics (HES) data for attendances across 18 EDs in Y&H from April 2011 to March 2014 were retrospectively analysed. HES A&E and Admitted Patient Care patient records data were linked to describe the entire patient pathway. The population studied was adult patients attending type 1 EDs, comparing those ≥75 years with those under 75. Data analysed included arrival mode, presentation time, time in ED, outcome (admitted/discharged), admission length of stay, International Classification of Diseases 10th Revision (ICD-10) and cause codes related to admission. Short-stay admissions and admissions with potentially avoidable conditions (identified by ICD-10 codes and cause codes) were identified. Comparative analysis was undertaken between sites. RESULTS: There were 3 736 541 ED attendances, of which 625 772 (16.7%) were ≥75 years. Older patients were significantly more likely to attend via ambulance than the younger cohort (OR 7.7, 95% CI 7.6 to 7.7), and had significantly longer median stays within ED (195 vs 136 min, p<0.001) and increased likelihood of admission (OR 4.5, 95% CI 4.5 to 4.6). Short-stay admissions accounted for 28.3% of older adult admissions. 37.3% of older adult admissions were with conditions that were potentially avoidable, accounting for 42.3% of short-stay admissions. There was regional variation in the proportions of older adults admitted (between 34.3% and 40.9%). DISCUSSION: Large numbers of older adults present to EDs mainly by ambulance. Significant proportions are admitted for short periods with conditions that might potentially be managed outside of hospital. Variation across the region warrants further study.

Altered cortical microarchitecture in patients with monoclonal gammopathy of undetermined significance.

Patients with monoclonal gammopathy of undetermined significance (MGUS) are at increased fracture risk, and we have previously shown that MGUS patients have altered trabecular bone microarchitecture compared with controls. However, there are no data on whether the porosity of cortical bone, which may play a greater role in bone strength and the occurrence of fractures, is increased in MGUS. Thus, we studied cortical porosity and bone strength (apparent modulus) using high-resolution peripheral quantitative computed tomography imaging of the distal radius in 50 MGUS patients and 100 age-, gender-, and body mass index-matched controls. Compared with controls, MGUS patients had both significantly higher cortical porosity (+16.8%; P < .05) and lower apparent modulus (-8.9%; P < .05). Despite their larger radial bone size, MGUS patients have significantly increased cortical bone porosity and reduced bone strength relative to controls. This increased cortical porosity may explain the increased fracture risk seen in MGUS patients.

The impact of surgery for vulval cancer upon health-related quality of life and pelvic floor outcomes during the first year of treatment: a longitudinal, mixed methods study.

OBJECTIVE: To measure the long-term impact of surgical treatment for vulval cancer upon health-related quality of life and pelvic floor outcomes during the first year of therapy. METHODS: Prospective, longitudinal, mixed-methods study. Twenty-three women aged >18 years with a new diagnosis of vulval cancer were recruited. The EORTC QLQ C30, SF-36 and an electronic pelvic floor assessment questionnaire (ePAQ-PF) were administered at baseline (pre-treatment) and 3, 6, 9 and 12 months post-treatment. Mixed effects repeated measures models (all adjusted for age and BMI) were used to investigate changes over time and differences between cancer stage. Qualitative interviews were carried out with 11 of the women and analysed using a thematic approach. RESULTS: Mean age was 59.9 years (SD = 15.3; range = 23.8-86.6 yrs). Mean BMI was 30.0 (SD = 4.5; range = 24.4-38.2). Sixteen women had early (Stage 1 to 2B), and seven women had advanced stage disease (Stage 3 to 4B). Questionnaire scores revealed that physical and social functioning, fatigue, pain and general sex life were significantly worse at 12 months than pre-treatment (p = < 0.05). Qualitative analysis revealed multiple treatment side effects which were perceived as severe and enduring. Women with advanced vulval cancer had significantly worse SF-36 mental health scores at 12 months compared to women with early stage disease (p = 0.037). CONCLUSIONS: Surgery for vulval cancer has long-term implications which can be persistent 12 months post-treatment. High rates of morbidity relating to lymphoedema and sexual function re-enforce the need for specialist clinics to support women who suffer these complications. © 2015 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.

Rapid-throughput skeletal phenotyping of 100 knockout mice identifies 9 new genes that determine bone strength.

Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary phenotype data with quantitative x-ray microradiography, micro-computed tomography, statistical approaches and biomechanical testing in 100 unselected knockout mouse strains identified nine new genetic determinants of bone mass and strength. These nine new genes include five whose deletion results in low bone mass and four whose deletion results in high bone mass. None of the nine genes have been implicated previously in skeletal disorders and detailed analysis of the biomechanical consequences of their deletion revealed a novel functional classification of bone structure and strength. The organ-specific and disease-focused strategy described in this study can be applied to any biological system or tractable polygenic disease, thus providing a general basis to define gene function in a system-specific manner. Application of the approach to diseases affecting other physiological systems will help to realize the full potential of the International Mouse Phenotyping Consortium.

Variation in centre-specific survival in patients starting renal replacement therapy in England is explained by enhanced comorbidity information from hospitalization data.

BACKGROUND: Unadjusted survival on renal replacement therapy (RRT) varies widely from centre to centre in England. Until now, missing data on case mix have made it impossible to determine whether this variation reflects genuine differences in the quality of care. Data linkage has the capacity to reduce missing data. METHODS: Modelling of survival using Cox proportional hazards of data returned to the UK Renal Registry on patients starting RRT for established renal failure in England. Data on ethnicity, socioeconomic status and comorbidity were obtained by linkage to the Hospital Episode Statistics database, using data from hospitalizations prior to starting RRT. RESULTS: Patients with missing data were reduced from 61 to 4%. The prevalence of comorbid conditions was remarkably similar across centres. When centre-specific survival was compared after adjustment solely for age, survival was below the 95% limit for 6 of 46 centres. The addition of variables into the multivariable model altered the number of centres that appeared to be 'outliers' with worse than expected survival as follows: ethnic origin four outliers, socioeconomic status eight outliers and year of the start of RRT four outliers. The addition of a combination of 16 comorbid conditions present at the start of RRT reduced the number of centres with worse than expected survival to one. CONCLUSIONS: Linked data between a national registry and hospital admission dramatically reduced missing data, and allowed us to show that nearly all the variation between English renal centres in 3-year survival on RRT was explained by demographic factors and by comorbidity.

The statistical interpretation of pilot trials: should significance thresholds be reconsidered?

BACKGROUND: In an evaluation of a new health technology, a pilot trial may be undertaken prior to a trial that makes a definitive assessment of benefit. The objective of pilot studies is to provide sufficient evidence that a larger definitive trial can be undertaken and, at times, to provide a preliminary assessment of benefit. METHODS: We describe significance thresholds, confidence intervals and surrogate markers in the context of pilot studies and how Bayesian methods can be used in pilot trials. We use a worked example to illustrate the issues raised. RESULTS: We show how significance levels other than the traditional 5% should be considered to provide preliminary evidence for efficacy and how estimation and confidence intervals should be the focus to provide an estimated range of possible treatment effects. We also illustrate how Bayesian methods could also assist in the early assessment of a health technology. CONCLUSIONS: We recommend that in pilot trials the focus should be on descriptive statistics and estimation, using confidence intervals, rather than formal hypothesis testing and that confidence intervals other than 95% confidence intervals, such as 85% or 75%, be used for the estimation. The confidence interval should then be interpreted with regards to the minimum clinically important difference. We also recommend that Bayesian methods be used to assist in the interpretation of pilot trials. Surrogate endpoints can also be used in pilot trials but they must reliably predict the overall effect on the clinical outcome.

The Risk Factors Associated with the Prevalence of Multimorbidity of Anaemia, Malaria, and Malnutrition among Children Aged 6-59 Months in Nigeria.

In the last ten years, multimorbidity in children under the age of five years has become an emerging health issue in developing countries. The study of multimorbidity of anaemia, malaria, and malnutrition (MAMM) among children in Nigeria has not received significant attention. This study aims to investigate what risk factors are associated with the prevalence of multimorbidity among children aged 6 to 59 months in Nigeria. This study used two nationally representative cross-sectional surveys, the 2018 Nigeria Demographic and Health Survey and the 2018 National Human Development Report. A series of multilevel mixed-effect ordered logistic regression models were used to investigate the associations between child/parent/household variables (at level 1), community-related variables (at level 2) and area-related variables (at level 3), and the multimorbidity outcome (no disease, one disease only, two or more diseases). The results show that 48.3% (4917/10,184) of the sample of children aged 6-59 months display two or more of the disease outcomes. Being a female child, the maternal parent having completed higher education, the mother being anaemic, the household wealth quintile being in the richest category, the proportion of community wealth status being high, the region being in the south, and place of residence being rural were among the significant predictors of MAMM (p < 0.05). The prevalence of MAMM found in this study is unacceptably high. If suitable actions are not urgently taken, Nigeria's ability to actualise SDG-3 will be in grave danger. Therefore, suitable policies are necessary to pave the way for the creation/development of integrated care models to ameliorate this problem.

The Intersection of a Child's Demographics and Household Socioeconomic Status in the Multimorbidity of Malaria, Anaemia, and Malnutrition among Children Aged 6-59 Months in Nigeria.

Multimorbidity of malaria, anemia, and malnutrition (MAMM) is a condition in which an individual has two or more of these health conditions, and is becoming an emergent public health concern in sub-Saharan African countries. The independent associations of a child's demographic variables and household socioeconomic (HSE) disparities with a child's health outcomes have been established in the literature. However, the effects of the intersection of these factors on MAMM, while accounting for other covariates, have not been studied. Therefore, this study aimed to determine how children's sex, age, and household socioeconomic status interact to explain the variations in MAMM among children aged 6-59 months in Nigeria. Data from the 2018 Nigeria Demographic and Health Survey and the 2018 National Human Development Report (NHDR) were used. This study included weighted samples of 10,184 children aged 6-59 months in Nigeria. A three-level multilevel mixed effect ordinal logistic regression model was used, such that individual characteristics at level 1 were nested in communities at level 2 and nested in states at level 3. Subsequently, predictive probability charts and average adjusted probability tables were used to interpret the intersectional effects. Five models were created in this scenario. Model 1 is the interaction between the child's sex and household wealth status; model 2 is the interaction between the child's sex and age; model 3 is the interaction between the child's age and household wealth status; model 4 has the three two-way interactions of the child's sex, age, and household wealth status; and model 5 includes model 4 and the three-way interactions between a child's sex, age, and household wealth quintiles; while accounting for other covariates in each of the models. The prevalence of children with a 'none of the three diseases' outcome was 17.3% (1767/10,184), while 34.4% (3499/10,184) had 'only one of the diseases', and 48.3% (4918/10,184) had 'two or more' MAMMs. However, in the multivariate analyses, model 3 was the best fit compared with other models, so the two-way interaction effects of a child's age and household wealth status are significant predictors in the model. Children aged 36-47 months living in the poorest households had a probability of 0.11, 0.18, and 0.32 of existing with MAMM above the probability of children of the same age who live in the middle class, more prosperous, and richest households, respectively, while all other covariates were held constant. Thus, the variation in the prevalence of MAMM in children of different ages differs depending on the household wealth quintile. In other words, in older children, the variations in MAMM become more evident between the richer and the poorer household quintiles. Therefore, it is recommended that policies that are geared toward economic redistribution will help bridge the disparities observed in the prevalence of multiple diseases among children aged 6-59 months in Nigeria.

Direct risk standardisation: a new method for comparing casemix adjusted event rates using complex models.

BACKGROUND: Comparison of outcomes between populations or centres may be confounded by any casemix differences and standardisation is carried out to avoid this. However, when the casemix adjustment models are large and complex, direct standardisation has been described as "practically impossible", and indirect standardisation may lead to unfair comparisons. We propose a new method of directly standardising for risk rather than standardising for casemix which overcomes these problems. METHODS: Using a casemix model which is the same model as would be used in indirect standardisation, the risk in individuals is estimated. Risk categories are defined, and event rates in each category for each centre to be compared are calculated. A weighted sum of the risk category specific event rates is then calculated. We have illustrated this method using data on 6 million admissions to 146 hospitals in England in 2007/8 and an existing model with over 5000 casemix combinations, and a second dataset of 18,668 adult emergency admissions to 9 centres in the UK and overseas and a published model with over 20,000 casemix combinations and a continuous covariate. RESULTS: Substantial differences between conventional directly casemix standardised rates and rates from direct risk standardisation (DRS) were found. Results based on DRS were very similar to Standardised Mortality Ratios (SMRs) obtained from indirect standardisation, with similar standard errors. CONCLUSIONS: Direct risk standardisation using our proposed method is as straightforward as using conventional direct or indirect standardisation, always enables fair comparisons of performance to be made, can use continuous casemix covariates, and was found in our examples to have similar standard errors to the SMR. It should be preferred when there is a risk that conventional direct or indirect standardisation will lead to unfair comparisons.

Did hospital mortality in England change from 2005 to 2010? A retrospective cohort analysis.

BACKGROUND: There is some evidence that hospital performance in England measured by the Dr Foster Hospital Standardised Mortality Ratio (HSMR) has improved substantially over the last 10 years. This study explores mortality in-hospital and up to 30 days post-discharge over a five year period to determine whether there have been improvements in case-mix adjusted mortality, to examine if any changes are due to changes in case-mix adjustment variables such as age, sex, method of admission and comorbidity, and to compare changes between hospital trusts. METHODS: Using Hospital Episode Statistics linked to mortality data from the Office for National Statistics the Summary Hospital-Level Mortality Index (SHMI) was calculated for all patients who were discharged or died in general acute hospital trusts in England for the period 01/04/2005 to 30/09/2010. RESULTS: During this five year period the number of admissions rose by 8% but deaths fell by 5%. The SHMI fell by 24% from 112 to 85 over the period, partly due to fewer deaths but partly due to increasing numbers predicted by the SHMI model. Excluding comorbidities from the model the SHMI fell by 18% from 108 to 89 over this period. The reduction was similar in emergency and elective admissions and in all other sub-groups examined. The average quarterly change in SHMI varied considerably between trusts (range: -4.4 to -0.2). CONCLUSIONS: As measured by the SHMI there has been a 24% improvement in mortality in acute general trusts in England over a period of five and a half years. Part of this improvement is an artificial effect caused by changes in the depth of coding of comorbidities and other effects due to change in case-mix or non-constant risk.

Home Waking Salivary Cortisone to Screen for Adrenal Insufficiency.

BACKGROUND: Worldwide, adults and children are at risk of adrenal insufficiency as a result of adrenal suppression from use of anti-inflammatory glucocorticoids and opiates, as well as infectious diseases. The adrenocorticotropin (ACTH) stimulation test is the reference standard for diagnosis of adrenal insufficiency but requires clinic attendance and venesection. Salivary cortisone reflects free serum cortisol, and samples can be collected at home and posted to a laboratory. We tested whether home waking salivary cortisone level could be used to screen for adrenal insufficiency. METHODS: A prospective, diagnostic accuracy study was performed in patients at high risk of adrenal insufficiency. Patients collected a home salivary sample on waking and then attended the clinical facility for an ACTH stimulation test. Salivary cortisone was measured by liquid chromatography­tandem mass spectrometry. Receiver-operating characteristic curves were computed, and positive and negative predictive values were calculated. RESULTS: Two hundred twenty patients were recruited. As measured by an ACTH stimulation test, the prevalence of adrenal insufficiency was 44%. The area under the receiver-operating characteristic curve for waking salivary cortisone as a predictor of adrenal insufficiency was 0.95 (95% confidence interval [CI], 0.92 to 0.97). Cutoffs to ensure a minimum of 95% sensitivity and specificity gave a negative predictive value of 96% (95% CI, 90 to 99) and a positive predictive value of 95% (95% CI, 87 to 99) to exclude and confirm adrenal insufficiency, respectively. Waking salivary cortisone data provided information similar to that of an ACTH stimulation test in 70% of participants. Eighty-three percent of patients preferred home salivary collection to clinic attendance. CONCLUSIONS: Home waking salivary cortisone sampling has accuracy for the diagnosis of adrenal insufficiency similar to that of a standard ACTH stimulation test. Patients found the at-home test to be more convenient than the hospital-based test. (Funded by the National Institute for Health Research.)

Statistical analysis of publicly funded cluster randomised controlled trials: a review of the National Institute for Health Research Journals Library.

BACKGROUND: In cluster randomised controlled trials (cRCTs), groups of individuals (rather than individuals) are randomised to minimise the risk of contamination and/or efficiently use limited resources or solve logistic and administrative problems. A major concern in the primary analysis of cRCT is the use of appropriate statistical methods to account for correlation among outcomes from a particular group/cluster. This review aimed to investigate the statistical methods used in practice for analysing the primary outcomes in publicly funded cluster randomised controlled trials, adherence to the CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines for cRCTs and the recruitment abilities of the cluster trials design. METHODS: We manually searched the United Kingdom's National Institute for Health Research (NIHR) online Journals Library, from 1 January 1997 to 15 July 2021 chronologically for reports of cRCTs. Information on the statistical methods used in the primary analyses was extracted. One reviewer conducted the search and extraction while the two other independent reviewers supervised and validated 25% of the total trials reviewed. RESULTS: A total of 1942 reports, published online in the NIHR Journals Library were screened for eligibility, 118 reports of cRCTs met the initial inclusion criteria, of these 79 reports containing the results of 86 trials with 100 primary outcomes analysed were finally included. Two primary outcomes were analysed at the cluster-level using a generalized linear model. At the individual-level, the generalized linear mixed model was the most used statistical method (80%, 80/100), followed by regression with robust standard errors (7%) then generalized estimating equations (6%). Ninety-five percent (95/100) of the primary outcomes in the trials were analysed with appropriate statistical methods that accounted for clustering while 5% were not. The mean observed intracluster correlation coefficient (ICC) was 0.06 (SD, 0.12; range, - 0.02 to 0.63), and the median value was 0.02 (IQR, 0.001-0.060), although 42% of the observed ICCs for the analysed primary outcomes were not reported. CONCLUSIONS: In practice, most of the publicly funded cluster trials adjusted for clustering using appropriate statistical method(s), with most of the primary analyses done at the individual level using generalized linear mixed models. However, the inadequate analysis and poor reporting of cluster trials published in the UK is still happening in recent times, despite the availability of the CONSORT reporting guidelines for cluster trials published over a decade ago.

Measuring the impact introducing NHS 111 online had on the NHS 111 telephone service and the wider NHS urgent care system: an observational study.

OBJECTIVES: To explore what impact introducing the National Health Service (NHS) 111 online service had on the number of phone calls to the NHS 111 telephone service and the NHS urgent care system. DESIGN: Observational study using a dose-response interrupted time series model and random-effects meta- analysis to estimate the average effect. SETTING AND PARTICIPANTS: NHS 111 telephone and online contacts for 18 NHS 111 area codes in England. NHS 111 telephone and online contacts data were collected between October 2010 to December 2019 and January 2018 to December 2019, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome: the number of triaged calls to the NHS 111 telephone service following the introduction of NHS 111 online. SECONDARY OUTCOMES: total calls to the NHS 111 telephone service, total number of emergency ambulance referrals or advice to contact 999, total number of advice to attend an emergency department or other urgent care treatment facility, and total number of advice to contact primary care. RESULTS: For triaged calls, the overall incidence rate ratio (IRR) per 1000 online contacts was 1.013 (95% CI: 0.996 to 1.029, p=0.127). For total calls, the overall IRR per 1000 online contacts was 1.008 (95% CI: 0.992 to 1.025, p=0.313). For emergency ambulance referrals or advice to contact 999, the overall IRR per 1000 online contacts was 1.067 (95% CI: 1.035 to 1.100, p<0.001). For advice to attend an emergency department or other urgent care treatment facility, the overall IRR per 1000 online contacts is 1.050 (95% CI: 1.010 to 1.092, p=0.014). And finally, for those advised to contact primary care, the overall IRR per 1000 online contacts is 1.051 (95% CI: 1.027 to 1.076, p<0.001). CONCLUSIONS: It was found that the NHS 111 online service has little impact on the number of triaged and total calls, suggesting that the workload for the NHS 111 telephone service has not increased or decreased as a result of introducing NHS 111 online. However, there was evidence to suggest an increase in the overall number of disposition recommendations (ambulance, emergency department and primary care) for NHS 111 telephone and online services combined following the introduction of the NHS 111 online service.

Recruitment, consent and retention of participants in randomised controlled trials: a review of trials published in the National Institute for Health Research (NIHR) Journals Library (1997-2020).

OBJECTIVES: To review the consent, recruitment and retention rates for randomised controlled trials (RCTs) funded by the UK's National Institute for Health Research (NIHR) and published in the online NIHR Journals Library between January 1997 and December 2020. DESIGN: Comprehensive review. SETTING: RCTs funded by the NIHR and published in the NIHR Journals Library. DATA EXTRACTION: Information relating to the trial characteristics, sample size, recruitment and retention. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the recruitment rate (number of participants recruited per centre per month). Secondary outcomes were the target sample size and whether it was achieved; consent rates (percentage of eligible participants who consented and were randomised) and retention rates (percentage of randomised participants retained and assessed with valid primary outcome data). RESULTS: This review identified 388 individual RCTs from 379 reports in the NIHR Journals Library. The final recruitment target sample size was achieved in 63% (245/388) of the RCTs. The original recruitment target was revised in 30% (118/388) of trials (downwards in 67% (79/118)). The median recruitment rate (participants per centre per month) was found to be 0.95 (IQR: 0.42-2.60); the median consent rate was 72% (IQR: 50%-88%) and the median retention rate was estimated at 88% (IQR: 80%-97%). CONCLUSIONS: There is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs. Although the majority of (6 out of 10) trials in this review achieved their final target sample; 3 out of 10 trials revised their original target sample size (downwards in 7 out of 10 trials). Investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections.

Supporting the ambulance service to safely convey fewer patients to hospital by developing a risk prediction tool: Risk of Adverse Outcomes after a Suspected Seizure (RADOSS)-protocol for the mixed-methods observational RADOSS project.

INTRODUCTION: Ambulances services are asked to further reduce avoidable conveyances to emergency departments (EDs). Risk of Adverse Outcomes after a Suspected Seizure seeks to support this by: (1) clarifying the risks of conveyance and non-conveyance, and (2) developing a risk prediction tool for clinicians to use 'on scene' to estimate the benefits an individual would receive if conveyed to ED and risks if not. METHODS AND ANALYSIS: Mixed-methods, multi-work package (WP) project. For WP1 and WP2 we shall use an existing linked data set that tracks urgent and emergency care (UEC) use of persons served by one English regional ambulance service. Risk tools are specific to clinical scenarios. We shall use suspected seizures in adults as an exemplar.WP1: Form a cohort of patients cared for a seizure by the service during 2019/2020. It, and nested Knowledge Exchange workshops with clinicians and service users, will allow us to: determine the proportions following conveyance and non-conveyance that die and/or recontact UEC system within 3 (/30) days; quantify the proportion of conveyed incidents resulting in 'avoidable ED attendances' (AA); optimise risk tool development; and develop statistical models that, using information available 'on scene', predict the risk of death/recontact with the UEC system within 3 (/30) days and the likelihood of an attendance at ED resulting in an AA.WP2: Form a cohort of patients cared for a seizure during 2021/2022 to 'temporally' validate the WP1 predictive models.WP3: Complete the 'next steps' workshops with stakeholders. Using nominal group techniques, finalise plans to develop the risk tool for clinical use and its evaluation. ETHICS AND DISSEMINATION: WP1a and WP2 will be conducted under database ethical approval (IRAS 307353) and Confidentiality Advisory Group (22/CAG/0019) approval. WP1b and WP3 have approval from the University of Liverpool Central Research Ethics Committee (11450). We shall engage in proactive dissemination and knowledge mobilisation to share findings with stakeholders and maximise evidence usage.