The Association Between Childhood Leukemia and Population Mixing: An Artifact of Focusing on Clusters?

BACKGROUND: Studies investigating the population-mixing hypothesis in childhood leukemia principally use two analytical approaches: (1) nonrandom selection of areas according to specific characteristics, followed by comparisons of their incidence of childhood leukemia with that expected based on the national average; and (2) regression analyses of region-wide data to identify characteristics associated with the incidence of childhood leukemia. These approaches have generated contradictory results. We compare these approaches using observed and simulated data. METHODS: We generated 10,000 simulated regions using the correlation structure and distributions from a United Kingdom dataset. We simulated cases using a Poisson distribution with the incidence rate set to the national average assuming the null hypothesis that only population size drives the number of cases. Selection of areas within each simulated region was based on characteristics considered responsible for elevated infection rates (population density and inward migration) and/or elevated leukemia rates. We calculated effect estimates for 10,000 simulations and compared results to corresponding observed data analyses. RESULTS: When the selection of areas for analysis is based on apparent clusters of childhood leukemia, biased assessments occur; the estimated 5-year incidence of childhood leukemia ranged between zero and eight per 10,000 children in contrast to the simulated two cases per 10,000 children, similar to the observed data. Performing analyses on region-wide data avoids these biases. CONCLUSIONS: Studies using nonrandom selection to investigate the association between childhood leukemia and population mixing are likely to have generated biased findings. Future studies can avoid such bias using a region-wide analytical strategy. See video abstract at, http://links.lww.com/EDE/B431.

Assessing the reporting of categorised quantitative variables in observational epidemiological studies.

BACKGROUND: One aspect to consider when reporting results of observational studies in epidemiology is how quantitative risk factors are analysed. The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines recommend that researchers describe how they handle quantitative variables when analysing data. For categorised quantitative variables, the authors are required to provide reasons and justifications informing their practice. We investigated and assessed the practices and reporting of categorised quantitative variables in epidemiology. METHODS: The assessment was based on five medical journals that publish epidemiological research. Observational studies published between April and June 2015 and investigating the relationships between quantitative exposures (or risk factors) and the outcomes were considered for assessment. A standard form was used to collect the data, and the reporting patterns amongst eligible studies were quantified and described. RESULTS: Out of 61 articles assessed for eligibility, 23 observational studies were included in the assessment. Categorisation of quantitative exposures occurred in 61% of these studies and reasons informing the practice were rarely provided. Only one article explained the choice of categorisation in the analysis. Transformation of quantitative exposures into four or five groups was common and dominant amongst studies using equally spaced categories. Dichotomisation was not popular; the practice featured in one article. Overall, the majority (86%) of the studies preferred ordered or arbitrary group categories. Other criterions used to decide categorical boundaries were based on established guidelines such as consensus statements and WHO standards. CONCLUSION: Categorisation of continuous variables remains a dominant practice in epidemiological studies. The reasons informing the practice of categorisation within published work are limited and remain unknown in most articles. The existing STROBE guidelines could provide stronger recommendations on reporting quantitative risk factors in epidemiology.

Hypofibrinolysis in type 2 diabetes: the role of the inflammatory pathway and complement C3.

AIMS/HYPOTHESIS: Plasminogen activator inhibitor-1 (PAI-1) has been regarded as the main antifibrinolytic protein in diabetes, but recent work indicates that complement C3 (C3), an inflammatory protein, directly compromises fibrinolysis in type 1 diabetes. The aim of the current project was to investigate associations between C3 and fibrinolysis in a large cohort of individuals with type 2 diabetes. METHODS: Plasma levels of C3, C-reactive protein (CRP), PAI-1 and fibrinogen were analysed by ELISA in 837 patients enrolled in the Edinburgh Type 2 Diabetes Study. Fibrin clot lysis was analysed using a validated turbidimetric assay. RESULTS: Clot lysis time correlated with C3 and PAI-1 plasma levels (r = 0.24, p < 0.001 and r = 0.22, p < 0.001, respectively). In a multivariable regression model involving age, sex, BMI, C3, PAI-1, CRP and fibrinogen, and using log-transformed data as appropriate, C3 was associated with clot lysis time (regression coefficient 0.227 [95% CI 0.161, 0.292], p < 0.001), as was PAI-1 (regression coefficient 0.033 [95% CI 0.020, 0.064], p < 0.05) but not fibrinogen (regression coefficient 0.003 [95% CI -0.046, 0.051], p = 0.92) or CRP (regression coefficient 0.024 [95% CI -0.008, 0.056], p = 0.14). No correlation was demonstrated between plasma levels of C3 and PAI-1 (r = -0.03, p = 0.44), consistent with previous observations that the two proteins affect different pathways in the fibrinolytic system. CONCLUSIONS/INTERPRETATION: Similarly to PAI-1, C3 plasma levels are independently associated with fibrin clot lysis in individuals with type 2 diabetes. Therefore, future studies should analyse C3 plasma levels as a surrogate marker of fibrinolysis potential in this population.

Do outcomes from transcatheter aortic valve implantation vary according to access route and valve type? The UK TAVI Registry.

OBJECTIVES: To determine whether outcomes from transcatheter aortic valve implantation (TAVI) vary according to access route and valve type in a real-world population. BACKGROUND: Registry and uncontrolled trial data have found that patients undergoing nonfemoral TAVI have higher early and late mortality. It is not clear whether worse outcomes relate directly to access route. There have been no direct comparisons of outcomes according to valve type. METHODS: Data were collected prospectively on 1,620 patients undergoing TAVI in the UK and compared in 4 groups: SAPIEN transfemoral (TF); SAPIEN transapical (TA); CoreValve TF, CoreValve subclavian. Univariable and multivariable regression analysis was performed to identify independent predictors of mortality. RESULTS: Mortality in patients undergoing SAPIEN TAVI via a TA approach was higher than with TF at 30 days (11.2% vs. 4.4%, P < 0.01), 1 year (28.7% vs. 18.1%, P = 0.01), and 2 years (56.0% vs. 43.5%, P = 0.01). Logistic EuroSCORE was higher in TA patients (22.5 ± 12.9% vs. 17.7 ± 11.1%, P < 0.0001). After multivariable analysis TA access was associated with increased mortality at 30 days (OR 2.56, 95% CI 1.46-4.48, P < 0.01) and 2 years (OR 1.75, 1.08-2.74, P = 0.02). There was no significant difference in mortality at any time-point between patients treated with SAPIEN (n = 812) and CoreValve (n = 808) prostheses. CoreValve-treated patients had a higher rate of permanent pacemaker implantation (23.1% vs. 7.2%, P < 0.0001), and grade ≥2 aortic regurgitation on postprocedure echocardiography (13.0% vs. 7.3%, P < 0.01). CONCLUSIONS: Patients undergoing TA TAVI experienced increased early and late mortality compared to a TF approach. Survival was not influenced by valve type.

Plasma thrombin-antithrombin complex, prothrombin fragments 1 and 2, and D-dimer levels are elevated after endovascular but not open repair of infrarenal abdominal aortic aneurysm.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is associated with hypercoagulability, evidenced by increased markers of coagulation activation, including thrombin-antithrombin complex (TAT), prothrombin fragments 1 and 2 (F1+2), and D-dimer. Our aim was to compare the effect of endovascular aneurysm repair (EVAR) and open aneurysm repair (OAR) on changes in coagulation activation markers after intervention. METHODS: Consecutive patients with AAAs reaching their intervention threshold in a tertiary vascular referral unit in the United Kingdom were invited to participate. The coagulation markers TAT, F1+2, and D-dimer were measured in venous blood collected at baseline and at 5 months after intervention. A forward stepwise multiple linear regression model was used to identify whether treatment by OAR or EVAR had an effect on changes in coagulation factors, independent of significant covariates. RESULTS: The study included 47 patients (14 EVAR, 33 OAR; 85% men) who were a median age of 76 years (range, 69.5-80 years). Aortic diameter at intervention was 5.9 cm (range, 5.5-6.8 cm). There were no significant differences in clinical, anthropometric, or hematologic parameters between groups. At baseline, TAT (P = .13), F1+2 (P = .08), and D-dimer (P = .11) were similar in EVAR and OAR patients. Postintervention, there was a significant increase in TAT (3.0 [2.1-6.0] vs 7.2 [6.3-8.4] ng/mL; P = .03), F1+2 (242 [189-323] vs 392 [312-494] ng/mL; P = .003), and D-dimer (457 [336-615] vs 1197 [840-1509] ng/mL; P = .002) in the EVAR group. No significant changes were observed after intervention in the OAR group. CONCLUSIONS: AAA-related hypercoagulability persists after intervention, with increased TAT, F1+2, and D-dimer levels after EVAR. These findings suggest a potential period of increased cardiovascular risk in the postoperative period after EVAR.

Cardiac resynchronization therapy in pacemaker-dependent patients with left ventricular dysfunction.

AIMS: Heart failure and left ventricular (LV) systolic dysfunction (LVSD) are common in patients with permanent pacemakers. The aim was to determine if cardiac resynchronization therapy (CRT) at the time of pulse generator replacement (PGR) is of benefit in patients with unavoidable RV pacing and LVSD. METHODS AND RESULTS: Fifty patients with unavoidable RV pacing, LVSD, and mild or no symptoms of heart failure, listed for PGR were randomized 1 : 1 to either standard RV-PGR (comparator) or CRT. The primary endpoint was the difference in change in LV ejection fraction (LVEF) between RV-PGR and CRT groups from baseline to 6 months. Secondary endpoints included peak oxygen consumption, quality of life, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. At 6 months there was a difference in change in median (interquartile range) LVEF [9 (6-12) vs. -1.5 (-4.5 to -0.8)%; P < 0.0001] between the CRT and RV-PGR arms. There were also improvements in exercise capacity (P = 0.007), quality of life (P = 0.03), and NT-proBNP (P = 0.007) in those randomized to CRT. After 809 (729-880) days, 17 patients had died or been hospitalized (6 in CRT group and 11 in the comparator RV-PGR group) and two patients in the RV-PGR arm had required CRT for deteriorating heart failure. Patients with standard RV-PGR had more days in hospital during follow-up than those in the CRT group [4 (2-7) vs. 11 (6-16) days; P = 0.047]. CONCLUSION: Performing CRT in pacemaker patients with unavoidable RV pacing and LVSD but without severe symptoms of heart failure, at the time of PGR, improves cardiac function, exercise capacity, quality of life, and NT-pro-BNP levels.

Target setting for elective infra-renal AAA surgery: A single mortality figure?

OBJECTIVES: One of the key standards set by the UK NAAASP is that centres performing elective abdominal aortic aneurysm (AAA) repair have a mortality rate of <6%. In light of this, and the current aim to reduce elective AAA repair mortality to 3.5% by 2013, we sought to investigate the statistical validity of such targets. METHODS: The National Vascular Database (NVD) was interrogated and the degree of AAA missing data and its geographical variation is described. Utilising published data from 2006 to 2008 a funnel plot was used to illustrate NHS Trust level data for current estimates of mortality rate. A binomial distribution model was applied to calculate variation in observed mortality rates in relation to number of patients treated, based on a "true" mortality rate of 3.5%. Funnel plots were constructed using simulated data-sets for units performing 10, 30, 50, 100 or 150 procedures annually with control-limits calculated using a cumulative probability distribution. Finally the effect of case-mix on mortality was modelled and shown graphically. RESULTS: The NVD AAA data set shows a range of data missingness across variables (median 22%, IQR 10-64%). High levels of missingness typically coincide with non-required, non-preferred variables however this is subject to geographical variation. Funnel plots of simulated data demonstrate that smaller units have greater variability in 3-year mortality (range 0.0-10.0%) than the largest units performing 150 procedures annually (1.3-5.6%). Around 20% of NVD variables are described as "preferred", these typically relate to clinical measurements and patient medications and would inform any risk model of mortality. Data missingness amongst these variables ranges from 5 to 50%. CONCLUSIONS: There are many problems with the use of a single mortality figure to assess performance. These include the natural statistical variability and the means by which "case-mix" is taken into consideration. This article calls for further research into mortality target setting and suggests strategies which may help provide solutions nationally and facilitate international comparison.

PIEZO1 and PECAM1 interact at cell-cell junctions and partner in endothelial force sensing.

Two prominent concepts for the sensing of shear stress by endothelium are the PIEZO1 channel as a mediator of mechanically activated calcium ion entry and the PECAM1 cell adhesion molecule as the apex of a triad with CDH5 and VGFR2. Here, we investigated if there is a relationship. By inserting a non-disruptive tag in native PIEZO1 of mice, we reveal in situ overlap of PIEZO1 with PECAM1. Through reconstitution and high resolution microscopy studies we show that PECAM1 interacts with PIEZO1 and directs it to cell-cell junctions. PECAM1 extracellular N-terminus is critical in this, but a C-terminal intracellular domain linked to shear stress also contributes. CDH5 similarly drives PIEZO1 to junctions but unlike PECAM1 its interaction with PIEZO1 is dynamic, increasing with shear stress. PIEZO1 does not interact with VGFR2. PIEZO1 is required in Ca2+-dependent formation of adherens junctions and associated cytoskeleton, consistent with it conferring force-dependent Ca2+ entry for junctional remodelling. The data suggest a pool of PIEZO1 at cell junctions, the coming together of PIEZO1 and PECAM1 mechanisms and intimate cooperation of PIEZO1 and adhesion molecules in tailoring junctional structure to mechanical requirement.

Continuous measures of driving performance on an advanced office-based driving simulator can be used to predict simulator task failure in patients with obstructive sleep apnoea syndrome.

INTRODUCTION: Some patients with obstructive sleep apnoea syndrome are at higher risk of being involved in road traffic accidents. It has not been possible to identify this group from clinical and polysomnographic information or using simple simulators. We explore the possibility of identifying this group from variables generated in an advanced PC-based driving simulator. METHODS: All patients performed a 90 km motorway driving simulation. Two events were programmed to trigger evasive actions, one subtle and an alert driver should not crash, while for the other, even a fully alert driver might crash. Simulator parameters including standard deviation of lane position (SDLP) and reaction times at the veer event (VeerRT) were recorded. There were three possible outcomes: 'fail', 'indeterminate' and 'pass'. An exploratory study identified the simulator parameters predicting a 'fail' by regression analysis and this was then validated prospectively. RESULTS: 72 patients were included in the exploratory phase and 133 patients in the validation phase. 65 (32%) patients completed the run without any incidents, 45 (22%) failed, 95 (46%) were indeterminate. Prediction models using SDLP and VeerRT could predict 'fails' with a sensitivity of 82% and specificity of 96%. The models were subsequently confirmed in the validation phase. CONCLUSIONS: Using continuously measured variables it has been possible to identify, with a high degree of accuracy, a subset of patients with obstructive sleep apnoea syndrome who fail a simulated driving test. This has the potential to identify at-risk drivers and improve the reliability of a clinician's decision-making.

Calcium channel blockers enhance sac shrinkage after endovascular aneurysm repair.

OBJECTIVE: Sac shrinkage is a surrogate marker of success after endovascular aneurysm repair (EVAR). We set out to determine if any common cardioprotective medications had a beneficial effect on sac shrinkage. METHODS: This retrospective observational study took place at Leeds Vascular Institute, a tertiary vascular unit in the Northern United Kingdom. The cohort comprised 149 patients undergoing EVAR between January 1, 2005, and December 31, 2008. Medication use was recorded at intervention (verified at study completion in 33 patients), and patients were monitored for 2 years. The main outcome measures were the effect of medication on sac shrinkage as determined by percentage change in maximal idealized cross-sectional area of the aneurysm at 1 month, 6 months, 1 year, and 2 years by linear regression model, in addition to 2-year endoleak and death rates determined by a binary logistic regression model. RESULTS: After exclusions, 112 patients, who were a median age of 78 years (interquartile range, 78-83 years), remained for analysis. The median Glasgow Aneurysm Score was 85 (interquartile range, 79-92). At 2 years, mortality was 13.4%, endoleak developed in 37.5%, and significant endoleak developed in 14.3%. Patients taking a calcium channel blocker had enhanced sac shrinkage, compared with those not taking a calcium channel blocker, by 6.6% at 6 months (-3.0% to 16.3%, P = .09), 12.3% at 1 year (2.9% to 21.7%, P = .008), and 13.1% at 2 years (0.005% to 26.2%, P = .007) independent of other medication use, graft type, endoleak development, or death. CONCLUSIONS: Enhanced sac shrinkage occurred after EVAR in patients taking calcium channel blockers. This warrants further study in other centers and at the molecular level.

The Effect of Endogenous Cushing Syndrome on All-cause and Cause-specific Mortality.

OBJECTIVE: We aimed to perform a systematic review and meta-analysis of all-cause and cause-specific mortality of patients with benign endogenous Cushing syndrome (CS). METHODS: The protocol was registered in PROSPERO (CRD42017067530). PubMed, EMBASE, CINHAL, Web of Science, and Cochrane Central searches were undertaken from inception to January 2021. Outcomes were the standardized mortality ratio (SMR), proportion, and cause of deaths. The I2 test, subgroup analysis, and meta-regression were used to assess heterogeneity across studies. RESULTS: SMR was reported in 14 articles including 3691 patients (13 Cushing disease [CD] and 7 adrenal CS [ACS] cohorts). Overall SMR was 3.0 (95% CI, 2.3-3.9; I2 = 80.5%) for all CS, 2.8 (95% CI, 2.1-3.7; I2 = 81.2%) for CD and 3.3 (95% CI, 0.5-6.6; I2 = 77.9%) for ACS. Proportion of deaths, reported in 87 articles including 19 181 CS patients (53 CD, 24 ACS, and 20 combined CS cohorts), was 0.05 (95% CI, 0.03-0.06) for all CS subtypes with meta-regression analysis revealing no differences between CS subtypes (P = .052). The proportion of deaths was 0.1 (10%) in articles published before 2000 and 0.03 (3%) in 2000 until the last search for CS (P < .001), CD (P < .001), and ACS (P = .01). The causes of death were atherosclerotic diseases and thromboembolism (43.4%), infection (12.7%), malignancy (10.6%), active disease (3.5%), adrenal insufficiency (3.0%), and suicide (2.2%). Despite improved outcomes in recent years, increased mortality from CS persists. The causes of death highlight the need to prevent and manage comorbidities in addition to treating hypercortisolism.

Association between operator volume and mortality in primary percutaneous coronary intervention.

BACKGROUND: There is a paucity of real-world data assessing the association of operator volumes and mortality specific to primary percutaneous coronary intervention (PPCI). METHODS: Demographic, clinical and outcome data for all patients undergoing PPCI in Leeds General Infirmary, UK, between 1 January 2009 and 31 December 2011, and 1 January 2013 and 31 December 2013, were obtained prospectively. Operator volumes were analysed according to annual operator PPCI volume (low volume: 1-54 PPCI per year; intermediate volume: 55-109 PPCI per year; high volume: ≥110 PPCI per year). Cox proportional hazards regression analyses were undertaken to investigate 30-day and 12-month all-cause mortality, adjusting for confounding factors. RESULTS: During this period, 4056 patients underwent PPCI, 3703 (91.3%) of whom were followed up for a minimum of 12 months. PPCI by low-volume operators was associated with significantly higher adjusted 30-day mortality (HR 1.48 (95% CI 1.05 to 2.08); p=0.02) compared with PPCI performed by high-volume operators, with no significant difference in adjusted 12-month mortality (HR 1.26 (95% CI 0.96 to 1.65); p=0.09). Comparisons between low-volume and intermediate-volume operators, and between intermediate and high-volume operators, showed no significant differences in 30-day and 12-month mortality. CONCLUSIONS: Low operator volume is independently associated with higher probability of 30-day mortality compared with high operator volume, suggesting a volume-outcome relationship in PPCI at a threshold higher than current recommendations.

Multiple imputation for completion of a national clinical audit dataset.

The Myocardial Ischaemia National Audit Project (MINAP) is a register of heart attacks covering 234 acute admitting hospitals in England and Wales. It is used to assess the extent to which hospitals are attaining the government targets for patients with heart attacks (myocardial infarction). MINAP is therefore of national importance in coronary care and of potential international importance for research. As with most observational databases, there is missing data in MINAP, which has the potential to bias statistical analyses. In this paper, we use multiple imputation to reduce the impact of missing data and we give details of how our imputation scheme was implemented. The key contribution of this paper is the provision of multiply completed datasets, suited to a range of analyses, that can be used to make efficient inferences without the distractions of missing data. Our work will assist MINAP in achieving its priority goal of providing useful data with which to analyse patient care.

Latent class regression improves the predictive acuity and clinical utility of survival prognostication amongst chronic heart failure patients.

The present study aimed to compare the predictive acuity of latent class regression (LCR) modelling with: standard generalised linear modelling (GLM); and GLMs that include the membership of subgroups/classes (identified through prior latent class analysis; LCA) as alternative or additional candidate predictors. Using real world demographic and clinical data from 1,802 heart failure patients enrolled in the UK-HEART2 cohort, the study found that univariable GLMs using LCA-generated subgroup/class membership as the sole candidate predictor of survival were inferior to standard multivariable GLMs using the same four covariates as those used in the LCA. The inclusion of the LCA subgroup/class membership together with these four covariates as candidate predictors in a multivariable GLM showed no improvement in predictive acuity. In contrast, LCR modelling resulted in a 18-22% improvement in predictive acuity and provided a range of alternative models from which it would be possible to balance predictive acuity against entropy to select models that were optimally suited to improve the efficient allocation of clinical resources to address the differential risk of the outcome (in this instance, survival). These findings provide proof-of-principle that LCR modelling can improve the predictive acuity of GLMs and enhance the clinical utility of their predictions. These improvements warrant further attention and exploration, including the use of alternative techniques (including machine learning algorithms) that are also capable of generating latent class structure while determining outcome predictions, particularly for use with large and routinely collected clinical datasets, and with binary, count and continuous variables.

Assessing the impact of body size in childhood and adolescence on blood pressure: an application of partial least squares regression.

BACKGROUND: Recent studies have found that postnatal catch-up growth might have a stronger impact than birth size on health in later life. Because growth is a continuing process, the challenge is to tease out the impact of body size at different critical phases. Ordinary least squares regression cannot differentiate the effects of birth size, growth, and current body size simultaneously, because growth is generally defined as the difference between birth size and current size, giving rise to perfect collinearity. METHODS: This paper aims to describe and justify the use of a novel approach, partial least squares, to estimate life course effects of body size z-scores on later blood pressure, using longitudinal data from a cohort of 960 Filipino boys. Body weight z-scores and changes in z-score weight were measured from birth to age 19 years, and systolic and diastolic blood pressures (BPs) were measured at age 19. RESULTS: In general, birth size had a very modest association with systolic BP. The early changes in z-scores between birth and the age of 2 years were positively associated with the outcome. Growth after age 8 had a larger effect than early growth, but the confidence intervals are generally large. For diastolic BP, the association was similar for early and later growth. Current body size had the strongest relationships with both outcomes. CONCLUSION: By creating weighted composites of perfectly collinear variables as components, partial least squares estimates the life course effects of body size on later health according to the correlations between body size and health outcomes.

Face and content validity analysis of the Speech, Spatial and Qualities of Hearing Scale for Parents (SSQ-P) when used in a clinical service without interviews or week-long observation periods.

OBJECTIVES: To assess the face and content validity of the Speech, Spatial and Qualities of Hearing Scale for Parents (SSQ-P) when used in a clinical setting without the recommended interviews and observation periods. METHODS: SSQ-P responses completed by 145 parents of children with bilateral cochlear implants (aged between 5 and 16 years old) were analysed. To assess face validity, the proportion of missing/ambiguous and alternative responses was recorded for each of the 23 items. Where additional written comments were included in responses, a thematic-based analysis was used to identify reasons for the missing/ambiguous or alternative responses. Content validity was assessed using item response theory (IRT), with items having information score less than 0.5 and discrimination score less than 2.0 identified as poorly performing items. RESULTS: All items of the SSQ-P exhibited some proportion of missing/ambiguous or alternative responses, with six items having >10% missing/ambiguous or alternative responses. IRT identified thirteen items that performed poorly in terms of information and discrimination. These included four of the six items with the most missing/ambiguous or alternative responses. CONCLUSIONS: SSQ-P items that performed worse tended to describe scenarios that parents perceived as too specific, too vague or hazardous. Without the recommended administration via interviews following three week-long observation periods, parents found these items difficult to complete. The SSQ-P is therefore not recommended for use without the recommended administration method. However, several items performed well in terms of face and content validity, despite independent parent completion without formal observation periods. Thematic analysis suggested that minor re-wording might improve the face validity of items with high content validity but a high proportion of missing/ambiguous or alternative responses. Therefore, the results of the analyses form the basis on which a shortened version of the SSQ-P, more suitable for use in a clinical setting, could be developed in future studies.

Significance and importance: some common misapprehensions about statistics.

There are many common misapprehensions about statistics that occur in the literature. We are sure that the three misapprehensions we deal with in this short review are widespread. They concern: 1)what P values mean;2)what an insignificant result means, and what it does not mean; the question of the 'power' of a statistical test;3)the difference between importance and statistical significance.We produce no formulae or recipes for dealing with particular situations, instead we concentrate on the commonsense use of simple statistics. We emphasise that if the use of any but the simplest statistics is intended, it is much better to get proper statistical help before starting experiments, rather than afterwards.

Dose Dependency of Iatrogenic Glucocorticoid Excess and Adrenal Insufficiency and Mortality: A Cohort Study in England.

CONTEXT: Adrenal insufficiency and Cushing syndrome are known adverse events of glucocorticoids. However, no population estimates of dose-related risks are available. OBJECTIVE: To investigate dose-related risks of adrenal dysfunction and death in adults with six chronic inflammatory diseases treated with oral glucocorticoids. DESIGN AND SETTING: Retrospective, record-linkage, open-cohort study spanning primary and hospital care in England. PATIENTS: A total of 70,638 oral glucocorticoid users and 41,166 nonusers aged ≥18 years registered in 389 practices in 1998 to 2017. MAIN OUTCOME MEASURES: Incidence rates and hazard ratios (HRs) of diagnosed adrenal dysfunction and death. RESULTS: During a median follow-up of 5.5 years, 183 patients had glucocorticoid-induced adrenal insufficiency and 248 had glucocorticoid-induced Cushing syndrome. A total of 22,317 (31.6%) and 7544 (18.3%) deaths occurred among glucocorticoid users and nonusers, respectively. The incidence of all outcomes increased with higher current daily and cumulative doses. For adrenal insufficiency, the increases in HRs were 1.07 (95% CI: 1.04 to 1.09) for every increase of 5 mg per day and 2.25 (95% CI: 2.15 to 2.35) per 1000 mg of cumulative prednisolone-equivalent dose over the past year. The respective increases in HRs for Cushing syndrome were 1.09 (95% CI: 1.08 to 1.11) and 2.31 (95% CI: 2.23 to 2.40) and for mortality 1.26 (95% CI: 2.24 to 1.28) and 2.05 (95% CI: 2.04 to 2.06). CONCLUSION: We report a high glucocorticoid dose-dependent increased risk of adrenal adverse events and death. The low observed absolute risk of adrenal insufficiency highlights a potential lack of awareness and a need for increased physician and patient education about the risks of adrenal dysfunction induced by glucocorticoids.