Richard Jacques

Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT).

Measurements of change in bone mineral density (BMD) are thought to be weak predictors of treatment effect on the reduction of fracture risk. In this study we report an alternative year‐on‐year approach for the estimation of treatment effect explained by BMD in which we examine the relationship between fracture risk and the most recent change in BMD. We studied 7736 postmenopausal women (ages 65 to 89 years) who were participants in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON‐PFT) and were randomized to either intravenous administration of zoledronic acid or placebo. The percentage of treatment effect explained by change in total hip BMD was estimated using the alternative year‐on‐year approach and the standard approach of looking at change over 3 years. We also studied a subset of 1132 women in whom procollagen type 1 amino‐terminal propeptide (PINP) was measured at baseline and 12 months, to estimate the percentage of treatment effect explained by change in PINP. Regardless of the method used, the change in total hip BMD explained a large percentage of the effect of zoledronic acid in reducing new vertebral fracture risk (40%; 95% CI, 30% to 54%; for the 3‐year analysis). The treatment effects for nonvertebral fracture were not statistically significant for the year‐on‐year analysis but 3‐year change in BMD explained 61% (95% CI, 24% to 156%) of treatment effect. Change in PINP explained 58% (95% CI, 15% to 222%) of the effect of zoledronic acid in reducing new vertebral fracture risk. We conclude that our estimates of the percentage of treatment effect explained may be higher than in previous studies because of high compliance with zoledronic acid (due to its once‐yearly intravenous administration). Previous studies may have underestimated the relationship between BMD change and the effect of treatment on fracture risk.

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

BackgroundIn 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.

Substantial reductions in the number of diabetic ketoacidosis and severe hypoglycaemia episodes requiring emergency treatment lead to reduced costs after structured education in adults with Type 1 diabetes.

To determine the impact of structured education promoting flexible intensive insulin therapy on rates of diabetic ketoacidosis, and the costs associated with emergency treatment for severe hypoglycaemia and ketoacidosis in adults with Type 1 diabetes.

Developing a summary hospital mortality index: retrospective analysis in English hospitals over five years

Objectives To develop a transparent and reproducible measure for hospitals that can indicate when deaths in hospital or within 30 days of discharge are high relative to other hospitals, given the characteristics of the patients in that hospital, and to investigate those factors that have the greatest effect in changing the rank of a hospital, whether interactions exist between those factors, and the stability of the measure over time. Design Retrospective cross sectional study of admissions to English hospitals. Setting Hospital episode statistics for England from 1 April 2005 to 30 September 2010, with linked mortality data from the Office for National Statistics. Participants 36.5 million completed hospital admissions in 146 general and 72 specialist trusts. Main outcome measures Deaths within hospital or within 30 days of discharge from hospital. Results The predictors that were used in the final model comprised admission diagnosis, age, sex, type of admission, and comorbidity. The percentage of people admitted who died in hospital or within 30 days of discharge was 4.2% for males and 4.5% for females. Emergency admissions comprised 75% of all admissions and 5.5% died, in contrast to 0.8% who died after an elective admission. The percentage who died with a Charlson comorbidity score of 0 was 2% in contrast with 15% who died with a score greater than 5. Given these variables, the relative standardised mortality rates of the hospitals were not noticeably changed by adjusting for the area level deprivation and number of previous emergency visits to hospital. There was little evidence that including interaction terms changed the relative values by any great amount. Using these predictors the summary hospital mortality index (SHMI) was derived. For 2007/8 the model had a C statistic of 0.911 and accounted for 81% of the variability of between hospital mortality. A random effects funnel plot was used to identify outlying hospitals. The outliers from the SHMI over the period 2005-10 have previously been identified using other mortality indicators. Conclusion The SHMI is a relatively simple tool that can be used in conjunction with other information to identify hospitals that may need further investigation.

Leptin May Play a Role in Bone Microstructural Alterations in Obese Children

CONTEXT Bone mass is low and fracture risk is higher in obese children. Hormonal changes in relation to skeletal microstructure and biomechanics have not been studied in obese children. OBJECTIVE The objective of the study was to ascertain the relationships of obesity-related changes in hormones with skeletal microstructure and biomechanics. DESIGN High resolution peripheral quantitative computed tomography (HR-pQCT) was used to compare three-dimensional cortical and trabecular microstructure and biomechanics at load-bearing and nonload bearing sites in obese and lean children. The relationship between leptin, adiponectin, testosterone, estrogen, osteocalcin and sclerostin and skeletal microstructure was also determined. SETTING The study was conducted at a tertiary pediatric endocrine unit in the United Kingdom. PARTICIPANTS Obese and lean children were matched by gender and pubertal stage. RESULTS Radial cortical porosity (mean difference -0.01 [95% CI: -0.02, -0.004], P = .003) and cortical pore diameter (mean difference -0.005 mm [95% CI: -0.009, -0.001], P = .011) were lower in obese children. Tibial trabecular thickness was lower (mean difference -0.009 mm [95% CI: -0.014, -0.004], P = .003), and trabecular number was higher (mean difference 0.23 mm(-1) [95% CI: 0.08, 0.38], P = .004) in obese children. At the radius, fat mass percentage negatively correlated with cortical porosity (r = -0.57, P < .001) and pore diameter (r = -0.38, P = .02) and negatively correlated with trabecular thickness (r = -0.62, P < .001) and trabecular von Mises stress (r = -0.39, P = .019) at the tibia. No difference was observed in the other biomechanical parameters of the radius and tibia. Leptin was higher in obese children (805.3 ± 440.6 pg/ml vs 98.1 ± 75.4 pg/ml, P < .001) and was inversely related to radial cortical porosity (r = 0.60, 95% CI: [-0.80, -0.30], P < .001), radial cortical pore diameter (r = 0.51, 95% CI [-0.75, -0.16], P = .002), tibial trabecular thickness (r = 0.55, 95% CI: [-0.78, -0.21], P = .001) and tibial trabecular von Mises stress (r = -0.39, 95% CI: -0.65, 0.04, P = .02). CONCLUSION Childhood obesity alters radial and tibial microstructure. Leptin may direct these changes. Despite this, the biomechanical properties of the radius and tibia do not adapt sufficiently in obese children to withstand the increased loading potential from a fall. This may explain the higher incidence of fracture in obese children.

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.

Free 25-hydroxyvitamin D is low in obesity, but there are no adverse associations with bone health

BACKGROUND The mechanism and clinical significance of low circulating 25-hydroxyvitamin D [25(OH)D] in obese people are unknown. Low total 25(OH)D may be due to low vitamin D-binding proteins (DBPs) or faster metabolic clearance. However, obese people have a higher bone mineral density (BMD), which suggests that low 25(OH)D may not be associated with adverse consequences for bone. OBJECTIVE We sought to determine whether 1) vitamin D metabolism and 2) its association with bone health differ by body weight. DESIGN We conducted a cross-sectional observational study of 223 normal-weight, overweight, and obese men and women aged 25-75 y in South Yorkshire, United Kingdom, in the fall and spring. A subgroup of 106 subjects was also assessed in the winter. We used novel techniques, including an immunoassay for free 25(OH)D, a stable isotope for the 25(OH)D3 half-life, and high-resolution quantitative tomography, to make a detailed assessment of vitamin D physiology and bone health. RESULTS Serum total 25(OH)D was lower in obese and overweight subjects than in normal-weight subjects in the fall and spring (geometric means: 45.0 and 40.8 compared with 58.6 nmol/L, respectively; P < 0.001) but not in the winter. Serum 25(OH)D was inversely correlated with body mass index (BMI) in the fall and spring and in the winter. Free 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] were lower in obese subjects. DBP, the DBP genotype, and the 25(OH)D3 half-life did not differ between BMI groups. Bone turnover was lower, and bone density was higher, in obese people. CONCLUSIONS Total and free 25(OH)D and 1,25(OH)2D are lower at higher BMI, which cannot be explained by lower DBP or the shorter half-life of 25(OH)D3 We speculate that low 25(OH)D in obesity is due to a greater pool of distribution. Lower 25(OH)D may not reflect at-risk skeletal health in obese people, and BMI should be considered when interpreting serum 25(OH)D as a marker of vitamin D status.

The cost-effectiveness of the Dose Adjustment for Normal Eating (DAFNE) structured education programme: an update using the Sheffield Type 1 Diabetes policy model

To estimate the cost‐effectiveness of training in flexible intensive insulin therapy [as provided in the Dose Adjustment for Normal Eating (DAFNE) structured education programme] compared with no training for adults with Type 1 diabetes mellitus in the UK using the Sheffield Type 1 Diabetes Policy Model.

Recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the United Kingdom Health Technology Assessment Programme

Background Substantial amounts of public funds are invested in health research worldwide. Publicly funded randomised controlled trials (RCTs) often recruit participants at a slower than anticipated rate. Many trials fail to reach their planned sample size within the envisaged trial timescale and trial funding envelope. Objectives To review the consent, recruitment and retention rates for single and multicentre randomised control trials funded and published by the UKs National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme. Data sources and study selection HTA reports of individually randomised single or multicentre RCTs published from the start of 2004 to the end of April 2016 were reviewed. Data extraction Information was extracted, relating to the trial characteristics, sample size, recruitment and retention by two independent reviewers. Main outcome measures Target sample size and whether it was achieved; recruitment rates (number of participants recruited per centre per month) and retention rates (randomised participants retained and assessed with valid primary outcome data). Results This review identified 151 individually RCTs from 787 NIHR HTA reports. The final recruitment target sample size was achieved in 56% (85/151) of the RCTs and more than 80% of the final target sample size was achieved for 79% of the RCTs (119/151). The median recruitment rate (participants per centre per month) was found to be 0.92 (IQR 0.43–2.79) and the median retention rate (proportion of participants with valid primary outcome data at follow-up) was estimated at 89% (IQR 79–97%). Conclusions There is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs. Investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections.

Diurnal Differences in Risk of Cardiac Arrhythmias During Spontaneous Hypoglycemia in Young People With Type 1 Diabetes

OBJECTIVE Hypoglycemia may exert proarrhythmogenic effects on the heart via sympathoadrenal stimulation and hypokalemia. Hypoglycemia-induced cardiac dysrhythmias are linked to the “dead-in-bed syndrome,” a rare but devastating condition. We examined the effect of nocturnal and daytime clinical hypoglycemia on electrocardiogram (ECG) in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS Thirty-seven individuals with type 1 diabetes underwent 96 h of simultaneous ambulatory ECG and blinded continuous interstitial glucose monitoring (CGM) while symptomatic hypoglycemia was recorded. Frequency of arrhythmias, heart rate variability, and cardiac repolarization were measured during hypoglycemia and compared with time-matched euglycemia during night and day. RESULTS A total of 2,395 h of simultaneous ECG and CGM recordings were obtained; 159 h were designated hypoglycemia and 1,355 h euglycemia. A median duration of nocturnal hypoglycemia of 60 min (interquartile range 40–135) was longer than daytime hypoglycemia of 44 min (30–70) (P = 0.020). Only 24.1% of nocturnal and 51.0% of daytime episodes were symptomatic. Bradycardia was more frequent during nocturnal hypoglycemia compared with matched euglycemia (incident rate ratio [IRR] 6.44 [95% CI 6.26, 6.63], P < 0.001). During daytime hypoglycemia, bradycardia was less frequent (IRR 0.023 [95% CI 0.002, 0.26], P = 0.002) and atrial ectopics more frequent (IRR 2.29 [95% CI 1.19, 4.39], P = 0.013). Prolonged QTc, T-peak to T-end interval duration, and decreased T-wave symmetry were detected during nocturnal and daytime hypoglycemia. CONCLUSIONS Asymptomatic hypoglycemia was common. We identified differences in arrhythmic risk and cardiac repolarization during nocturnal versus daytime hypoglycemia in young adults with type 1 diabetes. Our data provide further evidence that hypoglycemia is proarrhythmogenic.