J Martin Bland

STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT

In clinical measurement comparison of a new measurement technique with an established one is often needed to see whether they agree sufficiently for the new to replace the old. Such investigations are often analysed inappropriately, notably by using correlation coefficients. The use of correlation is misleading. An alternative approach, based on graphical techniques and simple calculations, is described, together with the relation between this analysis and the assessment of repeatability.

Angiotensin-Converting Enzyme Gene Deletion Polymorphism: A New Risk Factor for Lacunar Stroke but not Carotid Atheroma

BACKGROUND AND PURPOSE A deletion (D)/insertion (I) polymorphism in the angiotensin-converting enzyme gene has been associated with myocardial infarction. Its relations to both stroke and atheroma remain uncertain. We examined its role as a risk factor in patients with cerebrovascular disease and its relation to carotid atheroma. METHODS One hundred one patients with symptomatic carotid artery territory cerebral ischemia were compared with 137 age-matched control subjects. In the patient group, carotid atheroma was assessed by measurement of degree of carotid stenosis and intima-media thickness with high-resolution duplex ultrasound. The D/I polymorphism was examined using the polymerase chain reaction. RESULTS D:I allele frequency was 0.59:0.41 in case subjects and 0.48:0.52 in control subjects (P = .01). The DD genotype was more common in patients with cerebrovascular disease compared with control subjects (36/101 versus 30/137, P = .02). The DD genotype conferred a relative risk of any type of cerebrovascular disease of 1.98 (95% confidence interval [CI], 1.11 to 3.51; P = .02). However, this was largely due to a strong association in the 18 patients with lacunar stroke, in whom the D:I ratio was 0.75:0.25 (P = .0097 versus control subjects). The odds ratio for lacunar stroke associated with the DD genotype was 5.6 (95% CI, 2.0 to 15.7) and was still significant at 4.40 (95% CI, 1.45 to 12.6; P < .009) after controlling for other risk factors. There was no significant association between angiotensin-converting enzyme genotype and cerebrovascular disease due to large-vessel stenosis. There was no association between genotype and age, sex, smoking history, diabetes, or cholesterol level. CONCLUSIONS The deletion polymorphism in the angiotensin-converting enzyme gene is a new independent risk factor for lacunar stroke but is not a risk factor for stroke associated with carotid stenosis.

Larval therapy for leg ulcers (VenUS II): randomised controlled trial

Objective To compare the clinical effectiveness of larval therapy with a standard debridement technique (hydrogel) for sloughy or necrotic leg ulcers. Design Pragmatic, three armed randomised controlled trial. Setting Community nurse led services, hospital wards, and hospital outpatient leg ulcer clinics in urban and rural settings, United Kingdom. Participants 267 patients with at least one venous or mixed venous and arterial ulcer with at least 25% coverage of slough or necrotic tissue, and an ankle brachial pressure index of 0.6 or more. Interventions Loose larvae, bagged larvae, and hydrogel. Main outcome measures The primary outcome was time to healing of the largest eligible ulcer. Secondary outcomes were time to debridement, health related quality of life (SF-12), bacterial load, presence of meticillin resistant Staphylococcus aureus, adverse events, and ulcer related pain (visual analogue scale, from 0 mm for no pain to 150 mm for worst pain imaginable). Results Time to healing was not significantly different between the loose or bagged larvae group and the hydrogel group (hazard ratio for healing using larvae v hydrogel 1.13, 95% confidence interval 0.76 to 1.68; P=0.54). Larval therapy significantly reduced the time to debridement (2.31, 1.65 to 3.2; P<0.001). Health related quality of life and change in bacterial load over time were not significantly different between the groups. 6.7% of participants had MRSA at baseline. No difference was found between larval therapy and hydrogel in their ability to eradicate MRSA by the end of the debridement phase (75% (9/12) v 50% (3/6); P=0.34), although this comparison was underpowered. Mean ulcer related pain scores were higher in either larvae group compared with hydrogel (mean difference in pain score: loose larvae v hydrogel 46.74 (95% confidence interval 32.44 to 61.04), P<0.001; bagged larvae v hydrogel 38.58 (23.46 to 53.70), P<0.001). Conclusions Larval therapy did not improve the rate of healing of sloughy or necrotic leg ulcers or reduce bacterial load compared with hydrogel but did significantly reduce the time to debridement and increase ulcer pain. Trial registration Current Controlled Trials ISRCTN55114812 and National Research Register N0484123692.

Short-Term Associations between Emergency Hospital Admissions for Respiratory and Cardiovascular Disease and Outdoor Air Pollution in London

There are concerns about the possible short-term effects of outdoor air pollution on health in the United Kingdom. In a study conducted during the time period between 1987 and 1992, investigators determined that ozone had small, but significant effects on emergency respiratory admissions. In the current study, the authors investigated associations between emergency admissions and outdoor air pollution for the time period from 1992 to 1994, inclusive, and compared the results with those obtained in the earlier study. The authors also examined particulate matter less than 10 microm in diameter (PM10) and carbon monoxide in the current study. Appropriate confounding factors, such as seasonal patterns, temperature, and humidity, were controlled for, and the authors used Poisson regression to estimate the association between daily emergency admissions for respiratory and cardiovascular diseases and ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, particles measured as Black Smoke, and PM10. Significant positive associations were found between emergency hospital admissions for respiratory disease and PM10 and sulfur dioxide, but such an association did not exist for ozone. The results were not significantly different from earlier results from London and were comparable with those determined in North America and Europe. Cardiovascular disease was associated with carbon monoxide and Black Smoke, but weaker associations existed with the other pollutants studied.

Restenosis After Carotid Angioplasty, Stenting, or Endarterectomy in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS)

Background and Purpose— Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) patients with carotid stenosis were randomized between endovascular treatment and endarterectomy. The rates of residual severe stenosis and restenosis and their contribution to recurrent symptoms was unclear. Methods— Endovascular patients were treated by balloon angioplasty alone (88%) or stenting (22%). Patches were used in 63% of endarterectomy patients. Carotid stenosis was categorized as mild (0% to 49%), moderate (50% to 69%), severe (70% to 99%), or occluded, using standardized Doppler ultrasound criteria at the examination closest to 1 month (n=283) and 1 year (n=347) after treatment. Recurrent cerebrovascular symptoms during follow-up were analyzed. Results— More patients had ≥70% stenosis of the ipsilateral carotid artery 1 year after endovascular treatment than after endarterectomy (18.5% versus 5.2%, P=0.0001). Residual severe stenosis was present in 6.5% of patients at 1 month after endovascular treatment. Between 1 month and 1 year, restenosis to ≥70% stenosis occurred in 10.5% of the endovascular group. After endarterectomy, 1.7% had residual severe stenosis at 1 month, and 2.5% developed severe restenosis. The results were significantly better after stenting compared with angioplasty alone at 1 month (P<0.001) but not at 1 year. Recurrent ipsilateral symptoms were more common in endovascular patients with severe stenosis (5/32 [15.6%]) compared with lesser degrees of stenosis at 1 year (11/141 [7.8%], P=0.02), but most were transient ischemic attacks and none were disabling or fatal strokes. There were no recurrent symptoms in the 9 endarterectomy patients with ≥70% stenosis at 1 year. Conclusions— Carotid stenosis 1 year after endovascular treatment is partly explained by poor initial anatomical results and partly by restenosis. The majority of patients were treated by angioplasty without stenting. Further randomized studies are required to determine whether newer carotid stenting techniques are associated with a lower risk of restenosis. The low rate of recurrent stroke in both endovascular and endarterectomy patients suggests that treatment of restenosis should be limited to patients with recurrent symptoms, but long term follow up data are required.

Adequacy and reporting of allocation concealment: review of recent trials published in four general medical journals

In randomised controlled trials, allocation concealment (separating the process of randomisation from the recruitment of participants) is important for rigorously designed trials.1–4 In 1996 many major medical journals adopted the CONSORT statement (whereby researchers have to include a short checklist of essential items and a flow diagram when reporting trials),5 and this move encouraged the reporting of allocation concealment. We reviewed the prevalence of adequate allocation concealment and its association with the statistical significance of trial results. We searched by hand four general medical journals (the BMJ, JAMA , the Lancet , and the New England Journal of Medicine ) to identify randomised controlled trials published from January 2002 to December 2002. We included articles if the authors reported that participants were randomised and if the trial was published as a full report with the results of the main analyses. We categorised articles according to whether allocation concealment was adequate (the person who executed the allocation sequence was different from the person who recruited …

Effect of albendazole treatments on the prevalence of atopy in children living in communities endemic for geohelminth parasites: a cluster-randomised trial

BACKGROUND Epidemiological studies have shown inverse associations between geohelminth (intestinal helminth) infection and atopy, leading to the suggestion that geohelminths might protect against allergy. Periodic deworming of school children with anthelmintics is a widely implemented intervention and has raised concerns that such programmes could increase allergy. We investigated the effect of repeated anthelmintic treatments with albendazole over 12 months on the prevalence of atopy and clinical indices of allergy. METHODS We did a cluster-randomised controlled trial in schoolchildren from 68 rural schools. Children were randomly assigned by school to either albendazole (34 schools, 1164 children) every 2 months for 12 months, or to no intervention (34 schools, 1209 children). The intervention schools received a total of seven albendazole treatments. The primary outcome was atopy at 12 months (allergen skin-test reactivity), and analysis was by intention-to-treat for whole-school analyses and per protocol for children. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN61195515. FINDINGS Data for analysis were available for all schools and from 67.4% (784 of 1164) and 70.1% (848 of 1209) of children in albendazole and no-treatment groups, respectively. Albendazole treatment caused large reductions in geohelminth prevalence over the study period (adjusted odds ratio 0.13, 95% CI 0.09-0.19, p<0.001), but there was no evidence that treatment was associated with an increase in atopy prevalence (0.97, 0.68-1.39, p=0.862), or clinical allergy (wheeze, 1.07, 0.54-2.11, p=0.848) in the albendazole compared with the no-treatment group. INTERPRETATION We saw no increase in the prevalence of atopy or clinical allergy associated with albendazole treatment. Deworming programmes for schoolchildren are unlikely to be accompanied by an increase in allergy.

Bronchodilator treatment and deaths from asthma: case-control study

Abstract Objective To investigate the association between bronchodilator treatment and death from asthma. Design Case-control study. Setting 33 health authorities or health boards in Great Britain. Participants 532 patients under age 65 who died from asthma and 532 controls with a hospital admission for asthma matched for period, age, and area. Main outcome measures Odds ratios for deaths from asthma associated with prescription of bronchodilators and other treatment, with sensitivity analyses adjusting for age at onset, previous hospital admissions, associated chronic obstructive lung disease, and number of other drug categories. Results After full adjustment, there were no significant associations with drugs prescribed in the 4-12 months before the index date. For prescriptions in the 1-5 years before, mortality was positively associated with inhaled short acting β2 agonists (odds ratio 2.05, 95% confidence interval 1.26 to 3.33) and inversely associated with antibiotics (0.59, 0.39 to 0.89). The former association seemed to be confined to those aged 45-64, and the association with antibiotics was more pronounced in those under 45. Significant age interactions across all periods suggested inverse associations with oral steroids confined to the under 45 age group. An inverse association with long acting β2 agonists and a positive association with methylxanthines in the 1-5 year period were non-significant. Conclusion There was no evidence of adverse effects on mortality with medium to long term use of inhaled long acting β2 agonist drugs. The association with short acting β2 agonists has several explanations, only one of which may be a direct adverse effect.

Clinical effectiveness of collaborative care for depression in UK primary care (CADET): cluster randomised controlled trial

Objective To compare the clinical effectiveness of collaborative care with usual care in the management of patients with moderate to severe depression. Design Cluster randomised controlled trial. Setting 51 primary care practices in three primary care districts in the United Kingdom. Participants 581 adults aged 18 years and older who met ICD-10 (international classification of diseases, 10th revision) criteria for a depressive episode on the revised Clinical Interview Schedule. We excluded acutely suicidal patients and those with psychosis, or with type I or type II bipolar disorder; patients whose low mood was associated with bereavement or whose primary presenting problem was alcohol or drug abuse; and patients receiving psychological treatment for their depression by specialist mental health services. We identified potentially eligible participants by searching computerised case records in general practices for patients with depression. Interventions Collaborative care, including depression education, drug management, behavioural activation, relapse prevention, and primary care liaison, was delivered by care managers. Collaborative care involved six to 12 contacts with participants over 14 weeks, supervised by mental health specialists. Usual care was family doctors’ standard clinical practice. Main outcome measures Depression symptoms (patient health questionnaire 9; PHQ-9), anxiety (generalised anxiety disorder 7; GAD-7), and quality of life (short form 36 questionnaire; SF-36) at four and 12 months; satisfaction with service quality (client satisfaction questionnaire; CSQ-8) at four months. Results 276 participants were allocated to collaborative care and 305 allocated to usual care. At four months, mean depression score was 11.1 (standard deviation 7.3) for the collaborative care group and 12.7 (6.8) for the usual care group. After adjustment for baseline depression, mean depression score was 1.33 PHQ-9 points lower (95% confidence interval 0.35 to 2.31, P=0.009) in participants receiving collaborative care than in those receiving usual care at four months, and 1.36 points lower (0.07 to 2.64, P=0.04) at 12 months. Quality of mental health but not physical health was significantly better for collaborative care than for usual care at four months, but not 12 months. Anxiety did not differ between groups. Participants receiving collaborative care were significantly more satisfied with treatment than those receiving usual care. The number needed to treat for one patient to drop below the accepted diagnostic threshold for depression on the PHQ-9 was 8.4 immediately after treatment, and 6.5 at 12 months. Conclusions Collaborative care has persistent positive effects up to 12 months after initiation of the intervention and is preferred by patients over usual care. Trial registration number ISRCTN32829227.

Unequal cluster sizes for trials in english and Welsh general practice : implications for sample size calculations

Cluster randomized trials are often used in primary care settings. In the U.K., general practices are usually the unit of allocation. The effect of variability in practice list size on sample size calculations is demonstrated using the General Medical Services Statistics for England and Wales, 1997. Summary statistics and tables are given to help design such trials assuming that a fixed proportion of patients are to be recruited from each cluster. Three different weightings of the cluster means are compared: uniform, cluster size and minimum variance weights. Minimum variance weights are shown to be superior to uniform, particularly when clusters are small, and to cluster size weights, particularly when clusters are large. Where there are large numbers of participants per cluster and cluster size weights are used, the power actually falls as more patients are recruited to large clusters. When minimum variance weights are used the increase in the design effect due to variation in list size is small, regardless of the size of intracluster correlation coefficient or the number of participants per cluster, provided there is no loss of randomized units. When the expected number of participants per practice is low a greater loss in power comes from practices which fail to recruit patients. A method to estimate the likely effect and allow for it is presented.